P2x4 receptor antagonist

ABSTRACT

The present invention relates to a diazepine derivative represented by the following general formula (I) (in the formula, R 1  and R 2  represent hydrogen atom and the like, or R 1  and R 2  bind together to form a naphthalene ring and the like together with the benzene ring to which they bind, R 3  and R 4  represent hydrogen atom and the like, R 5  represents hydrogen atom and the like, R 6  and R 7  represent hydrogen atom and the like, X represents C, CH or N, Y represents N, NH or C(═O), provided that when X is N, Y is not N or NH, and when X is C or CH, Y is not C(═O), Z represents oxygen atom or sulfur atom, A represents benzene ring and the like, B represents NHC(═O) and the like, D represents an atomic bond and the like, E represents an atomic bond and the like, G represents benzene which may be substituted and the like, and m represents an integer of 0 to 5) or a pharmacologically acceptable salt thereof, and a P2X4 receptor antagonist.

This is a Divisional of U.S. application Ser. No. 16/826,877, filed Mar.23, 2020, which is a Divisional of U.S. application Ser. No. 15/923,685,filed Mar. 16, 2018, which issued as U.S. Pat. No. 10,633,349, which isa Divisional of U.S. application Ser. No. 15/176,857, filed Jun. 8,2016, which issued as U.S. Pat. No. 9,969,700, which is a Divisional ofU.S. application Ser. No. 14/371,868, which issued as U.S. Pat. No.9,382,236, which is a U.S. National Stage of PCT/JP2013/050320, filedJan. 10, 2013, which claims priority to Japanese Application No.2012-005343, filed Jan. 13, 2012. The disclosures of each of theapplications listed above are incorporated by reference herein in theirentireties.

TECHNICAL FIELD

The present invention relates to a diazepine derivative having a P2X4receptor antagonist activity.

BACKGROUND ART

The ATP receptors are roughly classified into the P2X family of the ionchannel type receptors, and the P2Y family of the G protein couplingtype receptors, and seven kinds (P2X1 to P2X7) and eight kinds (P2Y1,P2Y2, P2Y4, P2Y6, and P2Y11 to P2Y14) of subtypes have so far beenreported, respectively.

The P2X4 receptor (Genebank No. X87763), a subtype of the P2X family,has been reported to be widely expressed in the central nervous system,and the like (Non-patent documents 1 to 5).

The onset mechanisms of intractable pains, including neurogenic pain,have not been precisely elucidated. If non-steroidal anti-inflammatorydrugs (NSAIDs) and morphine are not effective, no therapy is availablefor that pain. Therefore, very heavy physical and mental burden is givento patients and surrounding people. Neurogenic pain is often caused byinjury of a peripheral nerve or the central nerve, and it is caused by,for example, after-trouble of operation, cancer, spinal cord injury,herpes zoster, diabetic neuritis, trigeminal neuralgia, and the like.

Recently, Inoue et al. verified the involvement of the P2X receptor inneurogenic pain by using a spinal nerve-damaged animal model in whichallodynia can be detected. The authors described that nerve-damaged typeunusual pain (especially allodynia) is induced through the P2X4 receptorexpressed in the microglia cells of the spinal cord (Non-patentdocuments 6 and 7, and Patent document 1).

Therefore, a substance that inhibits the activity of the P2X4 receptoris expected to be a prophylactic or therapeutic agent for pains ofnociceptive pain, inflammatory pain, and neurogenic pain.

Patent document 2 reported that a benzofuro-1,4-diazepin-2-onederivative represented by the following general formula (A):

(in the formula, R₁ is a halogen, and R₂ is hydrogen, a halogen, nitro,cyano, C(O)—OR₃, C(O)—NR₄R₅, SO₂—OR₃, or SO₂—NR₄R₅, or alternatively, R₁is hydrogen, and R₂ is a halogen, nitro, cyano, C(O)—OR₃, C(O)—NR₄R₅,SO₂—OR₅, or SO₂—NR₄R₅) has a P2X4 receptor antagonist activity.

It was also reported that paroxetine, which is an antidepressant, alsohas a P2X4 receptor antagonist activity (Non-patent document 8).

The inventors of the present invention also found that anaphtho[1,2-e]-1,4-diazepin-2-one derivative represented by thefollowing formula (B):

and related compounds thereof has a P2X4 receptor antagonist activity,and filed patent applications (Patent documents 3, 4 and 5).

The compounds of Patent documents 3 to 5 mentioned above and thecompounds of the present invention represented by the general formula(I) mentioned later are distinguishable from each other in that, in theformer compounds, the substituent of the phenyl group at the 5-positionis hydroxy group, a halogen atom, an alkyl group having 1 to 8 carbonatoms, tetrazolyl group, or the like, whereas, in the latter compounds,the phenyl group or the heterocyclic ring represented by G is bound viaNHC(═O), NHC(═O)NH, or NHS(O)₂ represented by B. In addition, althoughPatent documents 4 and 5 describe an acylamino group having 2 to 8carbon atoms and an acylamino group having 2 to 8 carbon atoms andsubstituted with 1 to 3 halogen atoms as the substituent of theaforementioned phenyl group, they only refer to lower alkylcarbonylaminogroups such as acetylamino and trifluoromethylcarbonylamino groups asspecific examples thereof, and do not describe benzoylamino groupwherein G is phenyl group, and B is NHC(═O) and the like of thecompounds of the present invention represented by the general formula(I) mentioned later.

Further, Patent document 6 describes a naphtho[1,2-b]-1,4-diazepin-4-onederivative represented by the following formula (C):

However, although Patent document 6 describes that the compoundrepresented by the aforementioned formula (C) is used as a photographiccoupler, there is no description suggesting relation between such acompound and P2X4 receptor antagonist activity.

Further, Patent document 7 describes a 1,4-benzodiazepine derivativehaving a phosphodiesterase 2 inhibitory activity, which is representedby the formula (D):

However, this patent document does not describe that the compound of theformula (D) has a P2X4 inhibitory activity.

PRIOR ART REFERENCES Patent Documents

-   Patent document 1: Published U.S. Patent Application No. 20050074819-   Patent document 2: WO2004/085440-   Patent document 3: WO2008/023847-   Patent document 4: WO2010/093061-   Patent document 5: WO2010/090300-   Patent document 6: Published Japanese Patent Application (Kokai) No.    112-304437-   Patent document 7: WO2004/041258

Non-Patent Documents

-   Non-patent document 1: Buell et al. (1996) EMBO J., 15:55-62-   Non-patent document 2: Seguela et al. (1996) J. Neurosci.,    16:448-455-   Non-patent document 3: Bo et al. (1995) FEBS Lett., 375:129-133-   Non-patent document 4: Soto et al. (1996) Proc. Natl. Acad. Sci.    USA, 93:3684-3688-   Non-patent document 5: Wang et al. (1996) Biochem. Res. Commun.,    220:196-202-   Non-patent document 6: M. Tsuda et al. (2003) Nature, 424, 778-783-   Non-patent document 7: Jeffrey A. M, Coull et al, (2005) Nature,    438, 1017-1021-   Non-patent document 8: The 49th Convention of The Japanese Society    for Neurochemistry (2006), Program Lecture Abstract P3-N-114

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

An object of the present invention is to provide a diazepine derivativerepresented by the following general formula (I) having a P2X4 receptorantagonist activity.

Means for Solving the Problem

The present invention thus relates to a compound represented by thefollowing general formula (I), or a pharmacologically acceptable saltthereof:

(wherein, R¹ and R² may be the same or different, and represent hydrogenatom, an alkyl group having 1 to 8 carbon atoms, a cycloalkyl grouphaving 3 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms,an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8carbon atoms and substituted with 1 to 3 halogen atoms, an alkoxy grouphaving 1 to 8 carbon atoms and substituted with 1 to 3 halogen atoms, ahalogen atom, hydroxyl group, nitro group, cyano group, amino group, analkylamino group having 1 to 8 carbon atoms, a dialkylamino group having2 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms,carboxyl group, an acyl group having 2 to 8 carbon atoms, analkoxycarbonyl group (the alkoxy moiety has 1 to 8 carbon atoms), aphenyl group which may be substituted, a pyridyl group which may besubstituted, or an aralkyl group (the aryl moiety has 6 to 10 carbonatoms, and the alkylene moiety has 1 to 8 carbon atoms),

or

R¹ and R² may bind together to form a condensed ring selected fromnaphthalene ring, quinoline ring, isoquinoline ring,tetrahydronaphthalene ring, indane ring, tetrahydroquinoline ring, andtetrahydroisoquinoline ring together with the benzene ring to which theybind, and the ring constituted by R¹ and R² bound to each other,together with the carbon atoms to which R¹ and R² bind may besubstituted with 1 to 4 of the same or different substituents selectedfrom an alkyl group having 1 to 8 carbon atoms, a cycloalkyl grouphaving 3 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms,an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8carbon atoms and substituted with 1 to 3 halogen atoms, an alkoxy grouphaving 1 to 8 carbon atoms and substituted with 1 to 3 halogen atoms, ahalogen atom, hydroxyl group, nitro group, cyano group, amino group, analkylamino group having 1 to 8 carbon atoms, a dialkylamino group having2 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms,carboxyl group, an acyl group having 2 to 8 carbon atoms, analkoxycarbonyl group (the alkoxy moiety has 1 to 8 carbon atoms), and anaralkyl group (the aryl moiety has 6 to 10 carbon atoms, and thealkylene moiety has 1 to 8 carbon atoms),

R³ and R⁴ may be the same or different, and represent hydrogen atom, analkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl grouphaving 1 to 8 carbon atoms and substituted with 1 to 3 halogen atoms, analkoxy group having 1 to 8 carbon atoms and substituted with 1 to 3halogen atoms, a halogen atom, hydroxyl group, nitro group, cyano group,amino group, an alkylamino group having 1 to 8 carbon atoms, adialkylamino group having 2 to 8 carbon atoms, an acylamino group having2 to 8 carbon atoms, carboxyl group, an acyl group having 2 to 8 carbonatoms, an alkoxycarbonyl group (the alkoxy moiety has 1 to 8 carbonatoms), or an aralkyl group (the aryl moiety has 6 to 10 carbon atoms,and the alkylene moiety has 1 to 8 carbon atoms),

R⁵ represents hydrogen atom, an alkyl group having 1 to 8 carbon atoms,an alkenyl group having 2 to 8 carbon atoms, an alkyl group having 1 to8 carbon atoms and substituted with 1 to 3 halogen atoms, an alkyl grouphaving 1 to 8 carbon atoms and substituted with hydroxyl group, or anaralkyl group (the aryl moiety has 6 to 10 carbon atoms, and thealkylene moiety has 1 to 8 carbon atoms),

R⁶ and R⁷ may be the same or different, and represent hydrogen atom, analkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl grouphaving 1 to 8 carbon atoms and substituted with 1 to 3 halogen atoms, analkoxy group having 1 to 8 carbon atoms and substituted with 1 to 3halogen atoms, a halogen atom, hydroxyl group, or amino group,

X represents 0, CH or N,

Y represents N, NH or C(═O),

provided that when X is N, Y is not N, or NH, and

when X is C or CH, Y is not C(═O),

the double line consisting of the solid line and the broken linerepresents a single bond or a double bond,

Z represents oxygen atom or sulfur atom,

A represents benzene ring, pyridine ring, thiophene ring, pyrimidinering, naphthalene ring, quinoline ring, or indole ring, which may have 1to 4 of the same or different substituents selected from an alkyl grouphaving 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms,an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8carbon atoms and substituted with 1 to 3 halogen atoms, an alkoxy grouphaving 1 to 8 carbon atoms and substituted with 1 to 3 halogen atoms, ahalogen atom, hydroxyl group, nitro group, cyano group, amino group, analkylamino group having 1 to 8 carbon atoms, a dialkylamino group having2 to 8 carbon atoms, an aralkyl group (the aryl moiety has 6 to 10carbon atoms, and the alkylene moiety has 1 to 8 carbon atoms), phenylgroup, and pyridyl group, as a substituent, or represents an atomicbond,

B represents N(R⁸)C(═O), NHCONH, CON(R⁹), NHC(═S)NH, N(R¹⁰)SO₂,SO₂N(R¹¹), or OSO₂,

wherein R⁸, R⁹, R¹⁰ and R¹¹ represent hydrogen atom, an alkyl grouphaving 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atomsand substituted with 1 to 3 halogen atoms, an alkyl group having 1 to 8carbon atoms and substituted with hydroxyl group, or an aralkyl group(the aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1to 8 carbon atoms),

D represents an alkylene chain having 1 to 6 carbon atoms, which mayhave 1 to 4 of the same or different substituents selected from an alkylgroup having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbonatoms, an alkyl group having 1 to 8 carbon atoms and substituted with 1to 3 halogen atoms, an alkyl group having 1 to 8 carbon atoms andsubstituted with hydroxyl group, and an aralkyl group (the aryl moietyhas 6 to 10 carbon atoms, and the alkylene moiety has 1 to 8 carbonatoms), as a substituent, and may further have a double bond, orrepresents an atomic bond,

E represents O, S, NR¹², or an atomic bond,

wherein R¹² represents hydrogen atom, an alkyl group having 1 to 8carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkylgroup having 1 to 8 carbon atoms and substituted with 1 to 3 halogenatoms, an alkyl group having 1 to 8 carbon atoms and substituted withhydroxyl group, or an aralkyl group (the aryl moiety has 6 to 10 carbonatoms, and the alkylene moiety has 1 to 8 carbon atoms),

G represents piperazine, piperidine, morpholine, cyclohexane, benzene,naphthalene, quinoline, quinoxaline, benzimidazole, thiophene,imidazole, thiazole, oxazole, indole, benzofuran, pyrrole, pyridine, orpyrimidine, which may have 1 to 4 of the same or different substituentsselected from an alkyl group having 1 to 8 carbon atoms, an alkenylgroup having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbonatoms, an alkyl group having 1 to 8 carbon atoms and substituted with 1to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms andsubstituted with 1 to 3 halogen atoms, a halogen atom, hydroxyl group,nitro group, cyano group, amino group, an alkylamino group having 1 to 8carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an acylgroup having 2 to 8 carbon atoms, methylenedioxy group, carboxyl group,an alkylsulfinyl group having 1 to 6 carbon atoms, an alkylthio grouphaving 1 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbonatoms, an aralkyl group (the aryl moiety has 6 to 10 carbon atoms, andthe alkylene moiety has 1 to 8 carbon atoms), a phenyl group which maybe substituted, a pyridyl group which may be substituted, an imidazolylgroup which may be substituted, an oxazolyl group which may besubstituted, and a thiazolyl group which may be substituted, as asubstituent, and

m represents an integer of 0 to 5,

provided that when 10 and R² do not bind together to form a ring, thosecompounds are excluded wherein, X is C, Y is N, the double lineconsisting of the solid line and the broken line is a double bond, Z isoxygen atom, A is benzene ring, m is 0, B is C(═O)NH, E is an atomicbond, and G is phenyl group).

The present invention also relates to:

a compound represented by the following general formula (II), or apharmacologically acceptable salt thereof:

(wherein, in the formula,

represents naphthalene ring, quinoline ring, isoquinoline ring,tetrahydronaphthalene ring, indane ring, tetrahydroquinoline ring, ortetrahydroisoquinoline ring, these rings may be substituted with 1 to 4of the same or different substituents selected from an alkyl grouphaving 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms,an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8carbon atoms and substituted with 1 to 3 halogen atoms, an alkoxy grouphaving 1 to 8 carbon atoms and substituted with 1 to 3 halogen atoms, ahalogen atom, hydroxyl group, nitro group, cyano group, amino group, analkylamino group having 1 to 8 carbon atoms, a dialkylamino group having2 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms,carboxyl group, an acyl group having 2 to 8 carbon atoms, analkoxycarbonyl group (the alkoxy moiety has 1 to 8 carbon atoms), and anaralkyl group (the aryl moiety has 6 to 10 carbon atoms, and thealkylene moiety has 1 to 8 carbon atoms),

R^(3a) and R^(4b) may be the same or different, and represent hydrogenatom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, analkyl group having 1 to 8 carbon atoms and substituted with 1 to 3halogen atoms, an alkoxy group having 1 to 8 carbon atoms andsubstituted with 1 to 3 halogen atoms, a halogen atom, hydroxyl group,nitro group, cyano group, amino group, an alkylamino group having 1 to 8carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, anacylamino group having 2 to 8 carbon atoms, carboxyl group, an acylgroup having 2 to 8 carbon atoms, an alkoxycarbonyl group (the alkoxymoiety has 1 to 8 carbon atoms), or an aralkyl group (the aryl moietyhas 6 to 10 carbon atoms, and the alkylene moiety has 1 to 8 carbonatoms),

R^(5a) represents hydrogen atom, an alkyl group having 1 to 8 carbonatoms, an alkenyl group having 2 to 8 carbon atoms, an alkyl grouphaving 1 to 8 carbon atoms and substituted with 1 to 3 halogen atoms, analkyl group having 1 to 8 carbon atoms and substituted with hydroxylgroup, or an aralkyl group (the aryl moiety has 6 to 10 carbon atoms,and the alkylene moiety has 1 to 8 carbon atoms),

R^(6a) and R^(7a) may be the same or different, and represent hydrogenatom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, analkyl group having 1 to 8 carbon atoms and substituted with 1 to 3halogen atoms, an alkoxy group having 1 to 8 carbon atoms andsubstituted with 1 to 3 halogen atoms, a halogen atom, hydroxyl group,or amino group,

represents benzene ring, pyridine ring, thiophene ring, pyrimidine ring,naphthalene ring, quinoline ring, or indole ring, which may have 1 to 4of the same or different substituents selected from an alkyl grouphaving 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms,an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8carbon atoms and substituted with 1 to 3 halogen atoms, an alkoxy grouphaving 1 to 8 carbon atoms and substituted with 1 to 3 halogen atoms, ahalogen atom, hydroxyl group, nitro group, cyano group, amino group, analkylamino group having 1 to 8 carbon atoms, a dialkylamino group having2 to 8 carbon atoms, an aralkyl group (the aryl moiety has 6 to 10carbon atoms, and the alkylene moiety has 1 to 8 carbon atoms), phenylgroup, and pyridyl group, as a substituent,

B^(a) represents N(R^(8a))C(═O), NHCONH, CON(R^(9a)), NHC(═S)NH,N(R^(10a))SO₂, SO₂N(R^(11a)), or OSO₂,

wherein R^(8a), R^(9a), R^(10a) and R^(11a) represent hydrogen atom, analkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8carbon atoms and substituted with 1 to 3 halogen atoms, an alkyl grouphaving 1 to 8 carbon atoms and substituted with hydroxyl group, or anaralkyl group (the aryl moiety has 6 to 10 carbon atoms, and thealkylene moiety has 1 to 8 carbon atoms),

E^(a) represents O, S, NR^(12a), or an atomic bond,

wherein R^(12a) represents hydrogen atom, an alkyl group having 1 to 8carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkylgroup having 1 to 8 carbon atoms and substituted with 1 to 3 halogenatoms, an alkyl group having 1 to 8 carbon atoms and substituted withhydroxyl group, or an aralkyl group (the aryl moiety has 6 to 10 carbonatoms, and the alkylene moiety has 1 to 8 carbon atoms),

G^(a) represents piperazine, piperidine, morpholine, cyclohexane,benzene, naphthalene, quinoline, quinoxaline, benzimidazole, thiophene,imidazole, thiazole, oxazole, indole, benzofuran, pyrrole, pyridine, orpyrimidine, which may have 1 to 4 of the same or different substituentsselected from an alkyl group having 1 to 8 carbon atoms, an alkenylgroup having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbonatoms, an alkyl group having 1 to 8 carbon atoms and substituted with 1to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms andsubstituted with 1 to 3 halogen atoms, a halogen atom, hydroxyl group,nitro group, cyano group, amino group, an alkylamino group having 1 to 8carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an acylgroup having 2 to 8 carbon atoms, methylenedioxy group, carboxyl group,an alkylsulfinyl group having 1 to 6 carbon atoms, an alkylthio grouphaving 1 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbonatoms, an aralkyl group (the aryl moiety has 6 to 10 carbon atoms, andthe alkylene moiety has 1 to 8 carbon atoms), a phenyl group which maybe substituted, a pyridyl group which may be substituted, an imidazolylgroup which may be substituted, an oxazolyl group which may besubstituted, and a thiazolyl group which may be substituted, as asubstituent, and

n represents an integer of 0 to 5).

The present invention also relates to a P2X4 receptor antagonistcomprising the compound represented by the aforementioned generalformula (I) or (II), or a pharmacologically acceptable salt thereof asan active ingredient.

The present invention further relates to a prophylactic or therapeuticagent for neurogenic pain comprising the compound represented by theaforementioned general formula (I) or (II), or a pharmacologicallyacceptable salt thereof as an active ingredient.

MODES FOR CARRYING OUT THE INVENTION

Hereafter, the present invention will be explained in detail.

In this specification, examples of the alkyl group having 1 to 8 carbonatoms include methyl group, ethyl group, propyl group, isopropyl group,butyl group, i-butyl group, t-butyl group, pentyl group, hexyl group,and the like.

Examples of the cycloalkyl group having 3 to 8 carbon atoms includecyclopropyl group, cyclohexyl group, and the like,

Examples of the alkenyl group having 2 to 8 carbon atoms include allylgroup, and the like.

Examples of the alkoxy group having 1 to 8 carbon atoms include methoxygroup, ethoxy group, propoxy group, isopropoxy group, butoxy group,i-butoxy group, t-butoxy group, pentyloxy group, hexyloxy group, and thelike.

Examples of the alkyl group having 1 to 8 carbon atoms and substitutedwith 1 to 3 halogen atoms include methyl group, ethyl group, propylgroup, isopropyl group, butyl group, t-butyl group, and the like, whichaxe substituted with 1 to 3 of halogen atoms such as fluorine atom,chlorine atom, and bromine atom, and preferred examples includetrifluoromethyl group, chloromethyl group, 2-chloroethyl group,2-bromoethyl group, 2-fluoroethyl group, and the like.

Examples of the alkoxy group having 1 to 8 carbon atoms and substitutedwith 1 to 3 halogen atoms include methoxy group, ethoxy group, propoxygroup, isopropoxy group, butoxy group, t-butoxy group, and the like,which are substituted with 1 to 3 of halogen atoms such as fluorineatom, chlorine atom, and bromine atom, and preferred examples includetrifluoromethoxy group, chloromethoxy group, 2-chloroethoxy group,2-bromoethoxy group, 2-fluoroethoxy group, and the like.

Examples of the halogen atom include fluorine atom, chlorine atom,bromine atom, and the like.

Examples of the alkylamino group having 1 to 8 carbon atoms includemethylamino group, ethylamino group, and the like.

Examples of the dialkylamino group having 2 to 8 carbon atoms includedimethylamino group, diethylamino group, and the like.

Examples of the acylamino group having 2 to 8 carbon atoms includeacetylamino group.

Examples of the acyl group having 2 to 8 carbon atoms include acetylgroup, and the like.

Examples of the alkoxycarbonyl group (the alkoxy moiety has 1 to 8carbon atoms) include methoxycarbonyl group, and the like.

Examples of the aralkyl group (the aryl moiety has 6 to 10 carbon atoms,and the alkylene moiety has 1 to 8 carbon atoms) include benzyl group,and the like.

Examples of the alkyl group having 1 to 8 carbon atoms and substitutedwith hydroxyl group include 2-hydroxyethyl group, and the like.

Examples of the alkylsulfinyl group having 1 to 6 carbon atoms includemethanesulfinyl group, and the like.

Examples of the alkylthio group having 1 to 6 carbon atoms includemethylthio group, and the like.

Examples of the alkylsulfonyl group having 1 to 6 carbon atoms includemethanesulfonyl group, and the like.

Examples of the substituent of the phenyl group which may besubstituted, the pyridyl group which may be substituted, the imidazolylgroup which may be substituted, the oxazolyl group which may besubstituted, and the thiazolyl group which may be substituted include ahalogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy grouphaving 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atomsand substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8carbon atoms and substituted with 1 to 3 halogen atoms, and the like.

As the compounds of the present invention represented by theaforementioned general formula W, the following compounds are preferred.

(1) A compound represented by the aforementioned general formula (I), ora pharmacologically acceptable salt thereof, wherein R¹ and R² may bethe same or different, and are hydrogen atom, an alkyl group having 1 to8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxygroup having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbonatoms and substituted with 1 to 3 halogen atoms, an alkoxy group having1 to 8 carbon atoms and substituted with 1 to 3 halogen atoms, a halogenatom, hydroxyl group, nitro group, cyano group, amino group, a phenylgroup which may be substituted, a pyridyl group which may besubstituted, or an aralkyl group (the aryl moiety has 6 to 10 carbonatoms, and the alkylene moiety has 1 to 8 carbon atoms).(2) The compound represented by the aforementioned general formula (I),or a pharmacologically acceptable salt thereof, wherein R¹ and R² bindtogether to form naphthalene ring, or tetrahydronaphthalene ringtogether with the benzene ring to which they bind, and the benzene ringor the cyclohexene ring constituted by R¹ and R², bound to each other,together with the carbon atoms to which R¹ and R² bind may besubstituted with 1 to 4 of the same or different substituents selectedfrom an alkyl group having 1 to 8 carbon atoms, an alkenyl group having2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, analkyl group having 1 to 8 carbon atoms and substituted with 1 to 3halogen atoms, an alkoxy group having 1 to 8 carbon atoms andsubstituted with 1 to 3 halogen atoms, a halogen atom, hydroxyl group,nitro group, cyano group, amino group, an alkylamino group having 1 to 8carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, anacylamino group having 2 to 8 carbon atoms, carboxyl group, an acylgroup having 2 to 8 carbon atoms, an alkoxycarbonyl group (the alkoxymoiety has 1 to 8 carbon atoms), and an aralkyl group (the aryl moietyhas 6 to 10 carbon atoms, and the alkylene moiety has 1 to 8 carbonatoms).(3) The compound represented by the aforementioned general formula (I),or a pharmacologically acceptable salt thereof, wherein. R¹ and R² bindtogether to form naphthalene ring together with the benzene ring towhich they bind, and the benzene ring constituted by R¹ and R², bound toeach other, together with the carbon atoms to which R¹ and R² bind maybe substituted with 1 to 4 of the same or different substituentsselected from an alkyl group having 1 to 8 carbon atoms, an alkenylgroup having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbonatoms, an alkyl group having 1 to 8 carbon atoms and substituted with 1to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms andsubstituted with 1 to 3 halogen atoms, a halogen atom, hydroxyl group,and amino group,(4) The compound represented by the aforementioned general formula (I)or the compound according to any one of (1) to (3) mentioned above, or apharmacologically acceptable salt thereof, wherein R³ and R⁴ may be thesame or different, and are hydrogen atom, an alkyl group having 1 to 8carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxygroup having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbonatoms and substituted with 1 to 3 halogen atoms, an alkoxy group having1 to 8 carbon atoms and substituted with 1 to 3 halogen atoms, a halogenatom, hydroxyl group, nitro group, cyano group, amino group, or anaralkyl group (the aryl moiety has 6 to 10 carbon atoms, and thealkylene moiety has 1 to 8 carbon atoms).(5) The compound represented by the aforementioned general formula (I)or the compound according to any one of (1) to (4) mentioned above, or apharmacologically acceptable salt thereof, wherein R⁵ is hydrogen atom,an alkyl group having 1 to 8 carbon atoms, or an aralkyl group (the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 8carbon atoms).(6) The compound represented by the aforementioned general formula (I)or the compound according to any one of (1) to (4) mentioned above, or apharmacologically acceptable salt thereof, wherein R⁵ is hydrogen atom.(7) The compound represented by the aforementioned general formula (I)or the compound according to any one of (1) to (6) mentioned above, or apharmacologically acceptable salt thereof, wherein R⁶ and R⁷ may be thesame or different, and are hydrogen atom, an alkyl group having 1 to 8carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl grouphaving 1 to 8 carbon atoms and substituted with 1 to 3 halogen atoms, oran alkoxy group having 1 to 8 carbon atoms and substituted with 1 to 3halogen atoms.(8) The compound represented by the aforementioned general formula (I)or the compound according to any one of (1) to (6) mentioned above, or apharmacologically acceptable salt thereof, wherein both R⁶ and R⁷ arehydrogen atoms.(9) The compound represented by the aforementioned general formula (I)or the compound according to any one of (1) to (8) mentioned above, or apharmacologically acceptable salt thereof, wherein X is N, Y is C(═O),and the double line consisting of the solid line and the broken line isa single bond.(10) The compound represented by the aforementioned general formula (I)or the compound according to any one of (1) to (8) mentioned above, or apharmacologically acceptable salt thereof, wherein X is C, Y is N, andthe double line consisting of the solid line and the broken line is adouble bond.(11) The compound represented by the aforementioned general formula (I)or the compound according to any one of (1) to (10) mentioned above, ora pharmacologically acceptable salt thereof, wherein Z is oxygen atom.(12) The compound represented by the aforementioned general formula (I)or the compound according to any one of (1) to (11) mentioned above, ora pharmacologically acceptable salt thereof, wherein A is phenyl group,or pyridyl group, which may have 1 to 4 of the same or differentsubstituents selected from an alkyl group having 1 to 8 carbon atoms, analkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8carbon atoms, an alkyl group having 1 to 8 carbon atoms and substitutedwith 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atomsand substituted with 1 to 3 halogen atoms, a halogen atom, hydroxylgroup, nitro group, cyano group, amino group, an alkylamino group having1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, anaralkyl group (the aryl moiety has 6 to 10 carbon atoms, and thealkylene moiety has 1 to 8 carbon atoms), phenyl group, and pyridylgroup, as a substituent.(13) The compound represented by the aforementioned general formula (I)or the compound according to arty one of (1) to (11) mentioned above, ora pharmacologically acceptable salt thereof, wherein A is phenyl group,which may have 1 to 4 of the same or different substituents selectedfrom an alkyl group having 1 to 8 carbon atoms, an alkenyl group having2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, analkyl group having 1 to 8 carbon atoms and substituted with 1 to 3halogen atoms, an alkoxy group having 1 to 8 carbon atoms andsubstituted with 1 to 3 halogen atoms, a halogen atom, hydroxyl group,nitro group, cyano group, and amino group, as a substituent.(14) The compound represented by the aforementioned general formula W orthe compound according to any one of (1) to (11) mentioned above, or apharmacologically acceptable salt thereof, wherein A is an atomic bond.(15) The compound represented by the aforementioned general formula (I)or the compound according to any one of (1) to (14) mentioned above, ora pharmacologically acceptable salt thereof, wherein B is NHC(═O),NHCONH, CONH, NHC(═S)NH, NHSO₂, SO₂ NH, or OSO₂.(16) The compound represented by the aforementioned general formula (I)or the compound according to any one of (1) to (14) mentioned above, ora pharmacologically acceptable salt thereof, wherein B is NHC(═O),NHCONH, or NHSO₂(17) The compound represented by the aforementioned general formula (I)or the compound according to any one of (1) to (16) mentioned above, ora pharmacologically acceptable salt thereof, wherein D is an alkylenechain having 1 to 6 carbon atoms, which may have 1 to 4 of the same ordifferent substituents selected from an alkyl group having 1 to 8 carbonatoms, and an alkyl group having 1 to 8 carbon atoms and substitutedwith 1 to 3 halogen atoms, as a substituent, and may further have adouble bond.(18) The compound represented by the aforementioned general formula (I)or the compound according to any one of (1) to (16) mentioned above, ora pharmacologically acceptable salt thereof, wherein D is an atomicbond.(19) The compound represented by the aforementioned general formula (I)or the compound according to any one of (1) to (16) mentioned above, ora pharmacologically acceptable salt thereof, wherein E is an atomicbond.(20) The compound represented by the aforementioned general formula (I)or the compound according to any one of (1) to (19) mentioned above, ora pharmacologically acceptable salt thereof, wherein G is piperazine,piperidine, morpholine, cyclohexane, benzene, naphthalene, quinoline,quinoxaline, benzimidazole, thiophene, imidazole, thiazole, oxazole,indole, benzofuran, pyrrole, pyridine or pyrimidine, which may have 1 to4 of the same or different substituents selected from an alkyl grouphaving 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms,an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8carbon atoms and substituted with 1 to 3 halogen atoms, an alkoxy grouphaving 1 to 8 carbon atoms and substituted with 1 to 3 halogen atoms, ahalogen atom, hydroxyl group, nitro group, cyano group, amino group, analkylamino group having 1 to 8 carbon atoms, a dialkylamino group having2 to 8 carbon atoms, an acyl group having 2 to 8 carbon atoms,methylenedioxy group, carboxyl group, an alkylsulfonyl group having 1 to6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, and analkylsulfonyl group having 1 to 6 carbon atoms, as a substituent.(21) The compound represented by the aforementioned general formula (I)or the compound according to any one of (1) to (19) mentioned above, ora pharmacologically acceptable salt thereof, wherein G is benzene, whichmay have 1 to 4 of the same or different substituents selected from analkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl grouphaving 1 to 8 carbon atoms and substituted with 1 to 3 halogen atoms, analkoxy group having 1 to 8 carbon atoms and substituted with 1 to 3halogen atoms, a halogen atom, hydroxyl group, nitro group, cyano group,amino group, an alkylamino group having 1 to 8 carbon atoms, adialkylamino group having 2 to 8 carbon atoms, an acyl group having 2 to8 carbon atoms, methylenedioxy group, carboxyl group, an alkylsulfonylgroup having 1 to 6 carbon atoms, an alkylthio group having 1 to 6carbon atoms, and an alkylsulfonyl group having 1 to 6 carbon atoms, asa substituent.(22) The compound represented by the aforementioned general formula (I)or the compound according to any one of (1) to (21) mentioned above, ora pharmacologically acceptable salt thereof, wherein m is 0.

As the compounds of the present invention represented by theaforementioned general formula (II), the following compounds arepreferred.

(23) The compound represented by the aforementioned general formula(II), or a pharmacologically acceptable salt thereof, wherein

is naphthalene ring or tetrahydronaphthalene ring, which may besubstituted with 1 to 4 of the same or different substituents selectedfrom an alkyl group having 1 to 8 carbon atoms, an alkenyl group having2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, analkyl group having 1 to 8 carbon atoms and substituted with 1 to 3halogen atoms, an alkoxy group having 1 to 8 carbon atoms andsubstituted with 1 to 3 halogen atoms, a halogen atom, hydroxyl group,nitro group, cyano group, amino group, an alkylamino group having 1 to 8carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, anacylamino group having 2 to 8 carbon atoms, carboxyl group, an acylgroup having 2 to 8 carbon atoms, an alkoxycarbonyl group (the alkoxymoiety has 1 to 8 carbon atoms), and an aralkyl group (the aryl moietyhas 6 to 10 carbon atoms, and the alkylene moiety has 1 to 8 carbonatoms), as a substituent.(24) The compound represented by the aforementioned general formula an,or a pharmacologically acceptable salt thereof, wherein

is naphthalene ring, which may be substituted with 1 to 4 of the same ordifferent substituents selected from an alkyl group having 1 to 8 carbonatoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy grouphaving 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atomsand substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8carbon atoms and substituted with 1 to 3 halogen atoms, a halogen atom,hydroxyl group, and amino group, as a substituent.(25) The compound represented by the aforementioned general formula (II)or the compound according to (23) or (24) mentioned above, or apharmacologically acceptable salt thereof, wherein R^(3 a) and R^(4 a)may be the same or different, and are hydrogen atom, an alkyl grouphaving 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms,an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8carbon atoms and substituted with 1 to 3 halogen atoms, an alkoxy grouphaving 1 to 8 carbon atoms and substituted with 1 to 3 halogen atoms, ahalogen atom, hydroxyl group, nitro group, cyano group, amino group, oran aralkyl group (the aryl moiety has 6 to 10 carbon atoms, and thealkylene moiety has 1 to 8 carbon atoms).(26) The compound represented by the aforementioned general formula (II)or the compound according to any one of (23) to (25) mentioned above, ora pharmacologically acceptable salt thereof, wherein R^(5 a) is hydrogenatom, an alkyl group having 1 to 8 carbon atoms, or an aralkyl group(the aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1to 8 carbon atoms).(27) The compound represented by the aforementioned general formula (II)or the compound according to any one of (28) to (25) mentioned above, ora pharmacologically acceptable salt thereof, wherein R^(5 a) is hydrogenatom.(28) The compound represented by the aforementioned general formula (II)or the compound according to any one of (23) to (27) mentioned above, ora pharmacologically acceptable salt thereof, wherein R^(6 a) and R^(7 a)may be the same or different, and are hydrogen atom, an alkyl grouphaving 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms,an alkyl group having 1 to 8 carbon atoms and substituted with 1 to 3halogen atoms, or an alkoxy group having 1 to 8 carbon atoms andsubstituted with 1 to 3 halogen atoms.(29) The compound represented by the aforementioned general formula (II)or the compound according to any one of (23) to (27) mentioned above, ora pharmacologically acceptable salt thereof, wherein both R^(6a) andR^(7a) are hydrogen atoms.(30) The compound represented by the aforementioned general formula (H)or the compound according to any one of (23) to (29) mentioned above, ora pharmacologically acceptable salt thereof, wherein

is phenyl group, or pyridyl group, which may have 1 to 4 of the same ordifferent substituents selected from an alkyl group having 1 to 8 carbonatoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy grouphaving 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atomsand substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8carbon atoms and substituted with 1 to 3 halogen atoms, a halogen atom,hydroxyl group, nitro group, cyano group, amino group, an alkylaminogroup having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8carbon atoms, an aralkyl group (the aryl moiety has 6 to 10 carbonatoms, and the alkylene moiety has 1 to 8 carbon atoms), phenyl group,and pyridyl group, as a substituent.(31) The compound represented by the aforementioned general formula (II)or the compound according to any one of (23) to (29) mentioned above, ora pharmacologically acceptable salt thereof, wherein

is phenyl group, which may have 1 to 4 of the same or differentsubstituents selected from an alkyl group having 1 to 8 carbon atoms, analkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8carbon atoms, an alkyl group having 1 to 8 carbon atoms and substitutedwith 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atomsand substituted with 1 to 3 halogen atoms, a halogen atom, hydroxylgroup, nitro group, cyano group, and amino group, as a substituent.(32) The compound represented by the aforementioned general formula (I)or the compound according to any one of (23) to (29) mentioned above, ora pharmacologically acceptable salt thereof, wherein

is an atomic bond.(33) The compound represented by the aforementioned general formula anor the compound according to any one of (23) to (32) mentioned above, ora pharmacologically acceptable salt thereof, wherein B^(a) is NHC(═O),NHCONH, CONH, NHC(═S)NH, NHSO₂, SO₂ NH, or OSO₂.(34) The compound represented by the aforementioned general formula (I)or the compound according to any one of (23) to (32) mentioned above, ora pharmacologically acceptable salt thereof, wherein B^(a) is NHC(═O),NHCONH, or NHSO₂.(35) The compound represented by the aforementioned general formula (II)or the compound according to any one of (23) to (34) mentioned above, ora pharmacologically acceptable salt thereof, wherein E^(a) is an atomicbond.(36) The compound represented by the aforementioned general formula (II)or the compound according to any one of (23) to (35) mentioned above, ora pharmacologically acceptable salt thereof, wherein G^(a) ispiperazine, piperidine, morpholine, cyclohexane, benzene, naphthalene,quinoline, quinoxaline, benzimidazole, thiophene, imidazole, thiazole,oxazole, indole, benzofuran, pyrrole, pyridine, or pyrimidine, which mayhave 1 to 4 of the same or different substituents selected from an alkylgroup having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbonatoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having1 to 8 carbon atoms and substituted with 1 to 3 halogen atoms, an alkoxygroup having 1 to 8 carbon atoms and substituted with 1 to 3 halogenatoms, a halogen atom, hydroxyl group, nitro group, cyano group, aminogroup, an alkylamino group having 1 to 8 carbon atoms, a dialkylaminogroup having 2 to 8 carbon atoms, an acyl group having 2 to 8 carbonatoms, methylenedioxy group, carboxyl group, an alkylsulfinyl grouphaving 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbonatoms, and an alkylsulfonyl group having 1 to 6 carbon atoms, as asubstituent.(37) The compound represented by the aforementioned general formula (II)or the compound according to any one of (23) to (35) mentioned above, ora pharmacologically acceptable salt thereof, wherein G^(a) is benzene,which may have 1 to 4 of the same or different substituents selectedfrom an alkyl group having 1 to 8 carbon atoms, an alkenyl group having2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, analkyl group having 1 to 8 carbon atoms and substituted with 1 to 3halogen atoms, an alkoxy group having 1 to 8 carbon atoms andsubstituted with 1 to 3 halogen atoms, a halogen atom, hydroxyl group,nitro group, cyano group, amino group, an alkylamino group having 1 to 8carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an acylgroup having 2 to 8 carbon atoms, methylenedioxy group, carboxyl group,an alkylsulfinyl group having 1 to 6 carbon atoms, an alkylthio grouphaving 1 to 6 carbon atoms, and an alkylsulfonyl group having 1 to 6carbon atoms, as a substituent.(38) The compound represented by the aforementioned general formula (II)or the compound according to any one of (23) to (37) mentioned above, ora pharmacologically acceptable salt thereof, wherein n is 0.

Examples of the pharmacologically acceptable salts of the compoundsrepresented by the aforementioned general formulas (I) and (II) includehydrochlorides, and alkali metal salts such as those of sodium,potassium, and lithium.

Further, there may be optical isomers of the compounds of the presentinvention such as cis- and trans-isomers, enantiomers, and racemates,and all of these substances fall within the scope of the presentinvention.

The synthetic schemes of the compounds of the present inventionrepresented by the aforementioned general formula (I) or (II) are shownbelow.

The step from a compound represented by the general formula (i) to acompound represented by the general formula (m), which is a compound ofthe present invention, in the synthesis methods 1 and 2, the step from acompound represented by the general formula (u) to a compoundrepresented by the general formula (w), which is a compound of thepresent invention, in the synthesis method 3, the step from a compoundrepresented by the general formula (ab) to a compound represented by thegeneral formula (ac), which is a compound of the present invention, inthe synthesis method 4, the step from a compound represented by thegeneral formula (ae) to a compound represented by the general formula(af), which is a compound of the present invention, in the synthesismethod 5, and the amidation step from a compound represented by thegeneral formula (am) to a compound represented by the general formula(an), which is a compound of the present invention, in the synthesismethod 7 are performed by using a usual amidation reaction in which anamino compound is reacted with carboxylic acid, carboxylic acid halide,sulfonic acid halide or the like in the presence of pyridine, etc.

The step from a compound represented by the general formula (i) to acompound represented by the general formula (ai), which is a compound ofthe present invention, in the synthesis method 6 is performed byreacting an amino compound with an isocyanate compound orisothiocyanate.

The step from a compound represented by the general formula (au) to acompound represented by the general formula (av) or (aw), which is acompound of the present invention, in the synthesis method 8 isperformed by oxidizing a compound represented by the general formula(au) with an oxidizing agent such as MCPBA.

The compounds of the present invention represented by the aforementionedgeneral formulas (I) and (II) can be prepared by referring to theaforementioned synthesis methods and the examples mentioned later, aswell as the aforementioned patent documents, prior art references, andthe like.

Examples of typical compounds of the present invention obtained asdescribed above are mentioned below.

Examples of Typical Compounds (1)

(In the formula, B^(a) (substitution position), n, E^(a), and G^(a) areas shown in Tables 1 to 10)

TABLE 1 B^(a) (substitution position) n E^(a) G^(a) NHCO(4) 0 Atomicbond Phenyl NHCO(4) 0 Atomic bond (2-CF₃)Phenyl NHCO(4) 0 Atomic bond(3-Br)Phenyl NHCO(4) 0 Atomic bond (4-CF₃)Phenyl NHCO(4) 0 Atomic bond(2-Me)Phenyl NHCO(4) 0 Atomic bond (2,6-Me)Phenyl NHCO(4) 0 Atomic bond(2,6-Cl)Phenyl NHCO(4) 0 Atomic bond (3-Cl)Phenyl NHCO(4) 1 Atomic bondPhenyl NHC(=S)NH(4) 0 Atomic bond Phenyl NHCO(4) 0 Atomic bond(2,8-OMe)Phenyl NHCO(4) 0 Atomic bond (2-OMe)Phenyl NHCO(4) 1 Atomicbond (2-Cl)Phenyl NHCO(4) 0 Atomic bond (2,3-Me)Phenyl NHCO(4) 0 Atomicbond (2,5-Me)Phenyl NHCO(4) 0 Atomic bond (2-Cl,5-Br)Phenyl

TABLE 2 B^(a) (substitution position) n E^(a) G^(a) NHCO(4) 0 Atomicbond (2,4-Cl)Phenyl NHCO(4) 0 Atomic bond (2-OH)Phenyl NHCO(4) 0 Atomicbond (2,3-OH)Phenyl NHC(=O)NH(4) 0 Atomic bond Phenyl NHCO(4) 1 Atomicbond (2,6-Cl)Phenyl NHCO(4) 1 Atomic bond (2-OMe)Phenyl NHCO(4) 1 Atomicbond (2-OH)Phenyl NHC(=S)NH(4) 0 Atomic bond (2-Cl)Phenyl NHCO(4) 0Atomic bond (3-CF₃)Phenyl NHCO(4) 1 Atomic bond (2-CF₃)PhenylNHC(=O)NH(4) 0 Atomic bond (2-CI)Phenyl NHCO(4) 0 Atomic bond(2-Cl,3-OMe)Phenyl NHCO(4) 2 Atomic bond Phenyl NHCO(4) 0 Atomic bond3-Indolyl NHCO(4) 0 Atomic bond (2-Cl,3-OH)Phenyl NHCO(4) 1 O Phenyl

TABLE 3 B^(a) (substitution position) n E^(a) G^(a) NHCO(4) 1 Atomicbond (2-Cl,4-OMe)Phenyl NHCO(4) 0 Atomic bond (1-Me)Imidazol-2-ylNHCO(4) 1 Atomic bond (2,4-Cl)Phenyl NHCO(4) 1 Atomic bond(2-C1,4-OH)Phenyl NHCO(4) 1 Atomic bond Pyridin-3-yl NHCO(4) 0 Atomicbond Benzimidazol-2-yl NHCO(4) 0 Atomic bond (2-Cl)Phenyl NHCO(4) 0Atomic bond (2-Br)Phenyl NHCO(4) 0 Atomic bond (2-I)Phenyl NHCO(4) 1Atomic bond (2-Me)Phenyl NHCO(4) 0 Atomic bond Quinoxalin-2-yl NHCO(4) 0Atomic bond (5-Me)Thiophen-2-yl NHCO(3) 1 Atomic bond (2-Cl)PhenylNHCO(4) 0 Atomic bond (2,4,6-Me)Phenyl NHCO(4) 0 Atomic bond(2-Et)Phenyl NHC(=S)NH(4) 0 Atomic bond (2-Me)Phenyl

TABLE 4 B^(a) (substitution position) n E^(a) G^(a) NHCO(4) 0 Atomicbond (4-NMe₂)Phenyl NHCO(4) 1 O (2,4-Cl)Phenyl NHCO(4) 1 O (2-Me)PhenylNHCO(4) 0 Atomic bond (2-Ac)Phenyl NHCO(4) 0 Atomic bond (2-tBu)PhenylNHCO(3) 0 Atomic bond (2-I)Phenyl NHCO(4) 0 Atomic bond(1-Me)Piperidin-4-yl NHCO(4) 0 Atomic bond Benzofuran-2-yl NHCO(4) 0Atomic bond (1-Me)Indol-3-yl NHCO(4) 0 Atomic bond (2-allyl)PhenylNHCO(4) 0 Atomic bond (2-nPr)Phenyl NHCO(4) 0 Atomic bond (2-iPrO)PhenylNHCO(4) 0 Atomic bond (3-Me)Thiophen_2-yl NHCO(4) 1 O (2-Me,3-CI)PhenylNHCO(4) 0 Atomic bond (2-CF₃,4-F)Phenyl NHCO(4) 0 Atomic bond(2-OMe,4-F)Phenyl

TABLE 5 B^(a) (substitution position) n E^(a) G^(a) NHCO(4) 0 Atomicbond (2-OH,4-F)Phenyl NHCO(3) 1 Atomic bond (2-I)Phenyl NHCO(4) 0 Atomicbond (3-NMe₂)Phenyl NHCO(4) 0 Atomic bond (2-OMe,4-I)Phenyl NHCO(4) 0Atomic bond (2-OMe,6-F)Phenyl NHCO(4) 0 Atomic bond (2-OH,4-I)PhenylNHCO(4) 0 Atomic bond (2-OH,6-F)Phenyl NHCO(4) 0 Atomic bond (2-F)PhenylNHCO(4) 0 Atomic bond (2-NMe₂)Phenyl NHCO(4) 0 Atomic bond(2-OMe,6-Me)Phenyl NHCO(4) 0 Atomic bond (2-OH,6-Me)Phenyl NHCO(4) 2Atomic bond (2-Me)Phenyl CONH(4) 0 Atomic bond Phenyl CONH(4) 1 Atomicbond Phenyl NHCO(4) 2 Atomic bond (2-Cl)Phenyl CONH(4) 1 Atomic bond(2-Cl)Phenyl

TABLE 6 B^(a) (substitution position) n E^(a) G^(a) CONH(4) 0 Atomicbond (2-Cl)Phenyl NHCO(4) 0 Atomic bond (5-Br,2,3- methylenedioxy)PhenylNHCO(4) 0 Atomic bond (2-OMe,6-BrPhenyl NHCO(4) 0 Atomic bond(2-OH,6-Br)Phenyl NHCO(4) 0 Atomic bond (2-OMe,6-Cl)Phenyl NHCO(4) 0Atomic bond (2-OH,6-Cl)henyl NHCO(4) 0 Atomic bond (2-OH,6-OMe)PhenylNHCO(4) 0 Atomic bond (2-OMe,6-CF₃)Phenyl NHCO(4) 0 Atomic bond(2-OH,6-CF₃)Phenyl NHCO(4) 0 Atomic bond (2-Cl,5-SMe)Phenyl NHCO(4) 0Atomic bond (2-SMe)Phenyl NHCO(4) 0 Atomic bond (3-SMe)Phenyl NHCO(4) 0Atomic bond (2-OMe,6-Et)Phenyl NHCO(4) 0 Atomic bond (3-SO₂Me)PhenylNHCO(4) 0 Atomic bond (2-OH,6-Et)Phenyl NHCO(4) 0 Atomic bond(3-S(=O)Me)Phenyl

TABLE 7 B^(a) (substitution position) n E^(a) G^(a) NHCO(4) 0 Atomicbond (2-Cl,5-S(=O)Me)Phenyl NHCO(4) 0 Atomic bond (2-S(=O)Me)PhenylNHCO(4) 0 Atomic bond (3-Cl)Pyridin-2-yl NHCO(4) 0 Atomic bond(2-OMe,3-Cl)Phenyl NHCO(4) 0 Atomic bond (3-Me)Pyridin-2-yl NHCO(4) 0Atomic bond (2-OH,3-Cl)Phenyl NHCO(4) 0 Atomic bond (3-OH)Pyridin-2-ylNHCO(4) 0 Atomic bond (3-Vinyl)Pyridin-2-yl NHCO(4) 0 Atomic bond(2-Et)Pyridin-2-yl NHSO₂(4) 0 Atomic bond (2-NO₂)Phenyl NHSO₂(4) 0Atomic bond Phenyl NHSO₂(4) 0 Atomic bond (3-Br)Phenyl NHSO₂(4) 0 Atomicbond (3-OMe)Phenyl NHSO₂(3) 0 Atomic bond (2-NO₂)Phenyl NMeSO₂(3) 0Atomic bond (2-NO₂)Phenyl NHSO₂(3) 0 Atomic bond Naphthalen-2-yl

TABLE 8 B^(a) (substitution position) n E^(a) G^(a) NHSO₂(3) 0 Atomicbond Naphthalen-1-yl NHSO₂(4) 0 Atomic bond Cyclohexyl NHSO₂(4) 0 Atomicbond Pyridin-3-yl NHSO₂(4) 0 Atomic bond (4-iPr)Phenyl NHSO₂(4) 1 Atomicbond Phenyl NHSO₂(4) 0 Atomic bond Thiophen-2-yl NHSO₂(4) 0 Atomic bondNaphthalen-2-yl NBnSO₂(4) 0 Atomic bond (2-NO₂)Phenyl NMeSO₂(4) 0 Atomicbond (3-Br)Phenyl NMeSO₂(4) 0 Atomic bond (2-NO₂)PhenylN(CH₂CH₂OH)SO₂(4) 0 Atomic bond (2-NO₂)Phenyl NHSO₂(4) 1 Atomic bond(2-Cl)Phenyl NHSO₂(4) 1 Atomic bond (3-Br)Phenyl NHSO₂(4) 0 Atomic bond(2-CF₃)Phenyl NHSO₂(4) 1 Atomic bond (2-Br)Phenyl NHSO₂(4) 1 Atomic bond(2-Me)Phenyl

TABLE 9 B^(a) (substitution position) n E^(a) G^(a) NHSO₂(4) 1 Atomicbond (2-NO₂)Phenyl NHSO₂(4) 2 Atomic bond Phenyl NHSO₂(4) 1 Atomic bond(4-Cl)Phenyl NMeSO₂(4) 1 Atomic bond (2-CF₃)Phenyl NMeSO₂(4) 1 Atomicbond (2-Et)Phenyl NMeSO₂(4) 1 Atomic bond (2,3-Me)Phenyl NMeSO₂(4) 2Atomic bond (2-Cl)Phenyl NMeSO₂(4) 1 Atomic bond (2-NO₂)Phenyl NMeSO₂(4)1 Atomic bond (2-NH₂)Phenyl NMeSO₂(4) 1 Atomic bond (2-NMe₂)Phenyl

TABLE 10 B^(a) (substitution position) n E^(a) G^(a) NHCO(4) 0 Atomicbond Pyridin-4-yl NHCO(4) 1 O Pyridin-3-yl NHCO(4) 0 Atomic bondPyridin-3-yl NHCO(4) 0 Atomic bond (2-Me)Pyridin-3-yl NHCO(4) 0 Atomicbond (2-Cl)Pyridin-3-yl NHCO(4) 1 O Pyridin-2-yl NHCO(4) 0 Atomic bond(4-CF₃)Pyridin-3-yl NHCO(4) 0 Atomic bond (2-iPr)Phenyl

Examples of Typical Compounds (2)

(In the formula, B^(a) (substitution position), n, E^(a), and G^(a) areas shown in Tables 11 and 12)

TABLE 11 B^(a) (substitution position) n E^(a) G^(a) NHCO(4) 0 Atomicbond Cyclohexyl NHCO(4) 0 Atomic bond (6-Me)Pyridin-2-yl NHCO(4) 0Atomic bond (2-Me)Pyridin-3-yl NHCO(4) 0 Atomic bond (2-OMe,3-Me)PhenylNHCO(4) 0 Atomic bond (2,3-Cl)Phenyl NHCO(4) 0 Atomic bond(2-OH,3-Me)Phenyl NHCO(4) 0 Atomic bond (2-I)Phenyl NHCO(4) 1 Atomicbond (1-Me)Pyrrol-2-yl NHCO(4) 1 Atomic bond (2-tBu)Phenyl NHCO(4) 0Atomic bond (2-Isopropenyl)Phenyl NHCO(4) 0 Atomic bond (2-iPr)PhenylNHCO(4) 1 Atomic bond Morpholin-2-yl NHCO(4) 0 Atomic bond(2-Cl)Pyridin-2-yl

TABLE 12 B^(a) (substitution position) n E^(a) G^(a) NHSO₂(4) 0 Atomicbond (2-NO₂)Phenyl NMeSO₂(4) 0 Atomic bond (2-NO₂)Phenyl SO₂NH(4) 0Atomic bond Phenyl OSO₂(4) 0 Atomic bond (3-Br)Phenyl NHSO₂(4) 1 Atomicbond (2-Cl)Phenyl NHSO₂(4) 0 Atomic bond (3-Br)Phenyl NHSO₂(4) 0 Atomicbond (3-OMe)Phenyl NHSO₂(4) 1 Atomic bond (2,3-Cl)Phenyl NHSO₂(4) 1Atomic bond (2,6-Cl)Phenyl NHSO₂(4) 1 Atomic bond (2-I)Phenyl NMeSO₂(4)1 Atomic bond (2-Cl)Phenyl

Examples of Typical Compounds (3)

(In the formula, R¹, B¹ (substitution position), n, E^(a), and G^(a) areas shown in Table 13)

TABLE 13 B^(a) (substitution R¹ position) n E^(a) G^(a) 7-OMe NHCO(4) 0Atomic bond (2,3-Me)Phenyl 7-OH NHCO(4) 0 Atomic bond (2,3-Me)Phenyl6-Me NHCO(4) 0 Atomic bond (2,3-Me)Phenyl 6,7-Me NHCO(4) 0 Atomic bond(2-I)Phenyl 6-Et NHCO(4) 0 Atomic bond (2-I)Phenyl 7-Ph NHCO(4) 0 Atomicbond (2-Isopropyl)Phenyl 7-(Pyridin-3yl) NHCO(4) 0 Atomic bond(2-Isopropyl)Phenyl 7-(Pyridin-2yl) NHCO(4) 0 Atomic bond(2-Isopropyl)Phenyl 7-Cl NHSO₂(4) 0 Atomic bond (2-Isopropyl)Phenyl 7-BrNHSO₂(4) 0 Atomic bond (2-Isopropyl)Phenyl 7-CF₃ NHSO₂(4) 0 Atomic bond(2-Isopropyl)Phenyl H NHSO₂(4) 0 Atomic bond (2-Isopropyl)Phenyl6-Me,7-Br NHSO₂(4) 0 Atomic bond (2-Isopropyl)Phenyl 7-OMe NHSO₂(4) 1Atomic bond (2-Cl)Phenyl 7-OH NHSO₂(4) 1 Atomic bond (2-Cl)Phenyl 6-MeNHSO₂(4) 1 Atomic bond (2-Cl)Phenyl

Examples of Typical Compounds (4)

(In the formula, B^(a) (substitution position), n, E^(a), and G^(a) areas shown in Table 14.)

TABLE 14 B^(a) (substitution position) n E^(a) G^(a) NHCO 0 Atomic bond(2-Cl,3-OMe)Phenyl NHCO 0 Atomic bond (2-I)Phenyl NHSO₂ 1 Atomic bond(2-Cl)Phenyl NHSO₂ 1 Atomic bond (2-Cl)Phenyl

Examples of Typical Compounds (5)

(In the formula, B^(a) (substitution position), n, E^(a), and G^(a) areas shown in Table 15.)

TABLE 15 B^(a) (substitution position) n E^(a) G^(a) NHCO(4) 0 Atomicbond (2-Cl,3-OMe)Phenyl NHCO(4) 0 Atomic bond (2-Cl,3-OH)Phenyl NHCO(4)0 Atomic bond (2-tBu)Phenyl NHCO(4) 0 Atomic bond (2-Cl,6-OMe)PhenylNHCO(4) 0 Atomic bond (2-Cl,6-OH)Phenyl NHSO₂(3) 0 Atomic bond PhenylNHSO₂(4) 1 Atomic bond (2-Cl)Phenyl

Examples of Typical Compounds (6)

(In the formula, B (substitution position), D, E, and G are as shown inTable 16.)

TABLE 16 B (substitution position) D E G NHCO(4) C(Me)H Atomic bondPhenyl NHCO(4) C(Me)₂ Atomic bond Phenyl NHCO(4) CH═CH Atomic bondPhenyl NHCO(4) C(Me)H O Phenyl NHCO(4) C(Me)₂ O Phenyl NHCO(4) CH═CHAtomic bond (2-Me)Phenyl NHCO(4) CH═CH Atomic bond (2-Cl)Phenyl

Examples of Typical Compounds (7)

(In the formula, m (substitution position), B, D, E, and G are as shownin Table 17.)

TABLE 17 m (substitution position) B D E G 1(4) NHCO Atomic bond Atomicbond Phenyl 1(4) NHCO Atomic bond Atomic bond (2-Cl)Phenyl 1(4) NHSO₂CH₂ Atomic bond (2-Cl)Phenyl

Examples of Typical Compounds (8)

(In the formula, X^(a), Y^(a), B^(a) (substitution position), n, E^(a),and G^(a) are as shown Table 18.)

TABLE 18 B^(a) (substitution X^(a) Y^(a) position) n E^(a) G^(a) CH C—FNHCO(4) 0 Atomic bond (2,3-Me)Phenyl CH C—OH NHCO(4) 0 Atomic bond(2,3-Me)Phenyl CH C—F NHCO(4) 0 Atomic bond (2-I)Phenyl CH N NHCO(4) 0Atomic bond (2-I)Phenyl CH N NHCO(4) 0 Atomic bond Phenyl N CH NHCO(4) 0Atomic bond (2-I)Phenyl CH N NHCO(4) 0 Atomic bond (2-Cl)Phenyl CH NNHCO(4) 0 Atomic bond (2-OH)Phenyl CH N NHC(═O)NH(4) 0 Atomic bond(2-OH)Phenyl CH N NHCO(4) 0 Atomic bond (2-OH,6-Me)Phenyl CH N NHCO(4) 0Atomic bond (2-OH,6-Cl)Phenyl CH N NHCO(3) 0 Atomic bond(2-OH,6-Cl)Phenyl CH N NHCO(4) 0 Atomic bond (2-Cl)Pyridin-2-yl CH NNHCO(4) 1 Atomic bond (2-Cl)Pyridin-2-yl CH N NHCO(4) 0 Atomic bond(2-Me)Pyridin-2-yl CH C—OMe NHSO₂(4) 1 Atomic bond (2-Cl)Phenyl CH C—OHNHSO₂(4) 1 Atomic bond (2-Cl)Phenyl

Examples of Typical Compounds (9)

(In the formula, I=II-III=IV, B^(a) (substitution position), n, E^(a),and G^(a) are as shown Table 19.)

TABLE 19 B^(a) (substitution I = II-III = IV position) n E^(a) G^(a)N═CH—CH═CH NHCO(4) 0 Atomic bond (2-I)Phenyl CH═N—CH═CH NHCO(4) 0 Atomicbond (2-I)Phenyl CH═CH—N═CH NHCO(4) 0 Atomic bond (2-I)Phenyl CH═CH—CH═NNHCO(4) 0 Atomic bond (2-I)Phenyl N═CH—CH═CH NHCO(4) 1 O PhenylN═CH—CH═CH NHCO(3) 0 Atomic bond (2-I)Phenyl N═CH—CH═CH NHCO(4) 0 Atomicbond (2-Cl)Phenyl N═CH—CH═CH NHCO(4) 0 Atomic bond (2-OH)PhenylN═CH—CH═CH NHC(═O)NH(4) 0 Atomic bond (2-OH)Phenyl N═CH—CH═CH NHCO(4) 1O (2-OH,6-Me) Phenyl N═CH—CH═CH NHCO(4) 0 Atomic bond (2-OH,6-Cl)PhenylN═CH—CH═CH NHCO(3) 0 Atomic bond (2-OH,6-Cl)Phenyl N═CH—CH═CH NHCO(4) 0Atomic bond (2-Cl)Pyridin-2-yl N═CH—CH═CH NHCO(4) 1 Atomic bond(2-Cl)Pyridin-2-yl N═CH—CH═CH NHCO(4) 0 Atomic bond (2-Me)Pyridin-2-ylCH═CH—N═CH NHCO(4) 0 Atomic bond (2-Cl)Pyridin-3-yl

Examples of Typical Compounds (10)

(In the formula, I=II-III=IV, B^(a) (substitution position), n, B^(a),and G^(a) are as shown in Table 20.)

TABLE 20 B^(a) (substitution I = II-III = IV position) n Ea GaNH—CH₂—CH₂—CH₂ NHCO(4) 0 Atomic bond (2-I)Phenyl CH₂—NH—CH₂—CH₂ NHCO(4)0 Atomic bond (2-I)Phenyl CH₂—CH₂—NH—CH₂ NHCO(4) 0 Atomic bond(2-I)Phenyl CH₂—CH₂—CH₂—NH NHCO(4) 0 Atomic bond (2-I)PhenylCH₂—CH₂—NH—CH₂ NHCO(4) 1 O Phenyl CH₂—CH₂—NH—CH₂ NHCO(3) 0 Atomic bond(2-I)Phenyl CH₂—CH₂—NH—CH₂ NHCO(4) 0 Atomic bond (2-Cl)PhenylCH₂—CH₂—NH—CH₂ NHCO(4) 0 Atomic bond (2-Cl)Pyridin-3-yl CH₂—CH₂—NH—CH₂NHCO(4) 0 Atomic bond (2-OH)Phenyl CH₂—CH₂—NH—CH₂ NHC(═O) 0 Atomic bond(2-OH)Phenyl NH(4) CH₂—CH₂—NH—CH₂ NHCO(4) 1 O (2-OH,6-Me) PhenylCH₂—CH₂—NH—CH₂ NHCO(4) 0 Atomic bond (2-OH,6-Cl)Phenyl CH₂—CH₂—NH—CH₂NHCO(3) 0 Atomic bond (2-OH,6-Cl)Phenyl CH₂—CH₂—NH—CH₂ NHCO(4) 0 Atomicbond (2-Cl)Pyridin-2-yl CH₂—CH₂—NH—CH₂ NHCO(4) 1 Atomic bond(2-Cl)Pyridin-2-yl CH₂—CH₂—NH—CH₂ NHCO(4) 0 Atomic bond(2-Me)Pyridin-2-yl CH₂—CH₂—NH—CH₂ NHCO(4) 0 Atomic bond(2-Cl)Pyridin-3-yl

Examples of Typical Compounds (11)

(In the formula, R^(5a), B^(a) (substitution position), n, E^(a), andG^(a) are as shown Table 21.)

TABLE 21 B^(a) (substitution R^(5a) position) n E^(a) G^(a) Bn NBnSO₂(4)0 Atomic bond (2-NO₂)Phenyl Me NBnSO₂(4) 0 Atomic bond (2-NO₂)Phenyl EtNBnSO₂(4) 0 Atomic bond (2-NO₂)Phenyl

Hereafter, the pharmacological efficacies of the compounds of thepresent invention will be described.

The P2X4 receptor antagonist activity of the compounds of the presentinvention was measured as follows.

The ATP receptor (human P2X4) was introduced into the 1321N1 cells, andthe cells were used as a stable ATP receptor expression system. TheP2X4-expressing 1321N1 cells were inoculated on a 96 well plate,cultured under the conditions of 37° C. and 5% CO₂ for 24 hours, andused for calcium measurement. Fura-2 AM, which is a calcium fluorescentindicator, was dissolved in an extracellular fluid for calcium imaging,and the inoculated cells were treated with the solution, and leftstanding at room temperature for 45 minutes so that Fura-2 AM wasincorporated into the cells. For the measurement, a microplate reader,FLUOstar Optima (BMG Labtech), was used. The light emitted from a xenonlamp was passed through 340 nm and 380 nm filters, respectively, andirradiated on the cells, fluorescences of 510 nm, F340 and F380, emittedfrom the cells were measured, and change of the ratio F340/F380 was usedas an index of change of intracellular calcium level. The measurementwas performed by adding ATP to each well at a final concentration of 1μM, and observing the ATP-induced Ca²⁺ response over time. In themeasurement, a treatment with a test substance was performed 15 minutesbefore the addition of ATP, and the inhibition activity of the testsubstance was calculated by comparison of the result with the resultobtained in the absence of the test substance.

As clearly seen from the results for the compounds of Examples 215 and216, the compounds of the present invention showed superior P2X4receptor antagonist activity (Tables 22 and 23).

As clearly seen from the result for the compound of Example 217, thecompound of the present invention showed superior analgesic activity.

Therefore, the diazepine derivatives represented by the aforementionedgeneral formula (I) and (II), and pharmacologically acceptable saltsthereof have a P2X4 receptor antagonist activity, and accordingly, it isconsidered that they are useful as prophylactic or therapeutic agentsfor pains of nociceptive pain, inflammatory pain, and neurogenic pain.More specifically, they are useful as prophylactic and therapeuticagents for pains accompanying various cancers, pains accompanyingdiabetic nerve damage, pains accompanying viral diseases such as herpes,arthrosis deformans, and the like. The prophylactic or therapeutic agentof the present invention may be used together with other medicaments ifneeded, and may be used together with, for example, opioid analgesics(morphine, fentanyl), sodium channel blockers (Novocain, lidocaine),NSAIDs (aspirin, ibuprofen), and the like. Further, when it is used forcancerous pain, it may be used together with, for example, anticanceragents such as anticancer chemotherapeutic agents.

The compounds of the present invention can be administered to a human byan appropriate administration method, such as oral administration orparenteral administration.

For manufacturing pharmaceutical preparations containing the compoundsof the present invention, dosage forms such as tablets, granules,powders, capsules, suspensions, injections, and suppositories can beprepared by the methods usually used in the field of pharmaceuticalmanufacturing.

For manufacturing such preparations, in the case of tablets, forexample, usual excipients, disintegrating agents, binders, lubricants,dyes, and the like are used. Examples of excipient include lactose,D-mannitol, crystalline cellulose, glucose, and the like, examples ofdisintegrating agent include starch, carboxymethylcellulose calcium(CMC-Ca), and the like, examples of lubricant include magnesiumstearate, talc, and the like, and examples of binder includehydroxypropylcellulose (HPC), gelatin, polyvinylpyrrolidone (PVP), andthe like. For manufacturing injection, solvents, stabilizers, dissolvingaids, suspending agents, emulsifiers, soothing agents, buffering agents,preservatives, and the like are used.

As for the administration dose, the compounds of the present inventionas the active ingredient can usually be administered to an adult in adaily dose of about 0.01 to 100 mg in the case of injection, or a dailydose of 1 to 2000 mg in the case of oral administration, but the dosemay be increased or decreased depending on age, symptoms, and the like.

Hereafter, the present invention will be explained in more detail withreference to examples. However, the present invention is not limited tothese examples.

Example 15-(4-Benzoylaminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(1) tert-Butyl 4-(1-nitro-2-naphthylamino)phenylcarbamate

1-Nitro-2-naphthyl trifluoromethanesulfonate (20.26 g, 63.07 mmol),tert-butyl 4-aminophenylcarbamate (13.13 g, 63.07 mmol),triphenylphosphine (1.65 g, 6.31 mmol),tetrakis(triphenylphosphine)palladium(0) (3.64 g, 3.15 mmol), potassiumcarbonate (8.72 g, 63.07 mmol), and dry toluene (600 mL) were mixed, andthe mixture was refluxed by heating for 6 hours under a nitrogenatmosphere. After the reaction mixture was left to cool, the insolublematter was separated by filtration, and washed off with ethyl acetate.The organic layer was washed with saturated aqueous sodiumhydrogencarbonate, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (hexane/ethyl acetate=4/1), and thenrecrystallized from ethyl acetate/hexane to obtain the title compound(18.67 g, yield 78%) as yellow crystals.

¹H NMR (CDCl₃, 400 MHz) δ: 1.54 (9H, s), 6.53 (1H, s), 7.21 (2H, d, J=9Hz), 7.21 (1H, d, J=9 Hz), 7.37 (1H, t, J=7 Hz), 7.44 (2H, d, J=9 Hz),7.62 (1H, dt, J=1 Hz, 9 Hz), 7.68 (1H, d, J=7 Hz), 7.70 (1H, d, J=9 Hz),8.61 (1H, d, J=9 Hz), 9.67 (1H, s)

(2) tert-Butyl 4-(1-amino-2-naphthylamino)phenylcarbamate

tert-Butyl 4-(1-nitro-2-naphthylamino)phenylcarbamate (18.67 g, 49.21mmol) was dissolved in tetrahydrofuran (180 mL) and methanol (180 mL),the mixture was added with platinum oxide (360 mg), and the mixture wasstirred at room temperature for 2 hours under a hydrogen atmosphere. Thecatalyst was separated by filtration, then the solvent was evaporatedunder reduced pressure, and the residue was washed with methanol to givethe title compound (15.67 g, yield 91%) as off-white crystals.

¹H NMR (DMSO-d₆, 400 MHz) δ: 1.45 (9H, s), 5.25 (2H, br s), 6.62 (2H, d,J=9 Hz), 7.0-7.3 (5H, m), 7.3-7.4 (2H, m), 7.72 (1H, d, J=8 Hz), 8.06(1H, d, J=8 Hz), 8.90 (1H,

(3) 5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

tert-Butyl 4-(1-amino-2-naphthylamino)phenylcarbamate (3.00 g, 8.58mmol), and sodium hydrogencarbonate (2.16 g, 25.7 mmol) were suspendedin chloroform (60 mL), and the suspension was added dropwise with ethylmalonyl chloride (1.22 mL, 9.5 mmol) over 1 minute with stirring underice cooling. This reaction mixture was stirred for 1 hour under icecooling, and then added with water, the mixture was stirred for 10minutes, and the chloroform layer was dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure to give acrude product of ethyl3-[[2-[[4-[(tert-butoxycarbonyl)amino]phenyl]amino]-1-naphthyl]amino]-3-oxcpropionate(4 g) as brown crystals.

This crude product (4 g) was dissolved in dry tetrahydrofuran (172 mL),the solution was added with 60% sodium hydride (1.72 g, 42.9 mmol) over1 minute with stirring under ice cooling, and the mixture was stirredunder ice cooling for 30 minutes, and then at room temperature for 3hours. This reaction mixture was added with saturated aqueous ammoniumchloride with stirring under ice cooling, and the organic layer wasdried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure to obtain a crude product of5-(4-tert-butoxycarbonylaminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneg) as pale brown crystals.

This crude product (4 g) was suspended in dichloromethane (176 mL), thesuspension was added dropwise with trifluoroacetic acid (13.1 mL, 176nil,) over 10 minutes with stirring under ice cooling, and then themixture was stirred under ice cooling for 1 hour, and then at roomtemperature for 16 hours. The solvent was evaporated at roomtemperature, the residue was added with saturated aqueous sodiumhydrogencarbonate and ethyl acetate, and the mixture was stirred at roomtemperature for 2 hours. The precipitated crystals were taken byfiltration, and washed with water and then with ethyl acetate to givethe title compound (1.23 g, yield 45%) as brown crystals.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.10 (1H, d, J=12 Hz), 3.61 (1H, d, J=0.12Hz), 5.26 (2H, s), 6.58 (2H, d, J=9 Hz), 6.84 (2H, d, J=8 Hz), 7.04 (1H,d, J=9 Hz), 7.57 (1H, t, J=7 Hz), 7.6-7.7 (2H, m), 7.90 (1H, d, J=8 Hz),8.22 (1H, d, J=8 Hz), 10.80 (1H, s)

(4)5-(4-Benzoylaminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30mg, 0.095 mmol), dry pyridine (3 mL), and benzoyl chloride (35 μL, 0.3mmol) were mixed, and the mixture was stirred at room temperature for 4hours and 30 minutes. The reaction mixture was added with saturatedaqueous sodium hydrogencarbonate, the mixture was extracted withchloroform, and the organic layer was washed with saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gelchromatography (methanol/chloroform=1/10) to give the title compound (36mg, yield 91%) as white powder.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.70 (1H, (1, J=12Hz), 7.02 (1H, d, J=9 Hz), 7.21 (2H, d, J=9 Hz), 7.5-7.7 (6H, m), 7.85(2H, d, J=9 Hz), 7.9-8.0 (3H, m), 8.25 (1H, d, J=9 Hz), 10.38 (1H, s),10.90 (1H, s).

Example 25-[4-[(2-(Trifluoromethyl)benzoyl]aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (16mg, 0.050 mmol) obtained in Example 1, (3), and2-(trifluoromethyl)benzoyl chloride (16 mg, 0.077 mmol), the titlecompound (20 mg, yield 81%) was obtained as off-white crystals in thesame manner as that of Example 1, (4).

¹H NMR (CDCl₃, 400 MHz) δ: 3.57 (1H, d, J=11 Hz), 3.60 (1H, d, J=11 Hz),7.06 (1H, d, J=0.9 Hz), 7.2-7.4 (2H, m), 7.5-7.8 (10H, m), 7.87 (1H, d,J=9 Hz), 8.08 (1H, a, J=8 Hz), 8.61 (1H, s).

Example 35-[4-(3-Bromobenzoyl)aminophenyl]-1H-naplatho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (16mg, 0.050 mmol) obtained in Example 1, (3), and 3-bromobenzoyl chloride(17 mg, 0.077 mmol), the title compound (15 mg, yield 60%) was obtainedas off-white crystals in the same manner as that of Example 1, (4).

¹H NMR (CDCl₃, 400 MHz) δ: 3.61 (2H, s), 7.04 (1H, d, J=8 Hz), 7.25 (2H,d, J=8 Hz), 7.38 (1H, t, J=8 Hz), 7.5-7.7 (6H, m), 7.79 (1H, d, J=8 Hz),7.86 (1H, d, J=8 Hz), 7.93 (1H, s), 8.01 (1H, br t, J=1 Hz), 8.06 (1H,d, J=9 Hz), 8.30 (1H, br s).

Example 45-[4-[4-(Trifluoromethyl)benzoyl]aminophenyl]-1H-naphthol[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (16mg, 0.050 mmol) obtained in Example 1, (3), and4-(trifluoromethyl)benzoyl chloride (16 mg, 0.077 mmol), the titlecompound (10 mg, yield 41%) was obtained as white crystals in the samemanner as that of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.71 (1H, d, J=12Hz), 7.01 (1H, d, J=9 Hz), 7.24 (2H, d, J=9 Hz), 7.59 (1H, t, J=8 Hz),7.67 (1H, d, J=8 Hz), 7.70 (1H, d, J=9 Hz), 7.85 (2H, d, J=9 Hz), 7.91(2H, d, J=8 Hz), 8.15 (2H, d, J=9 Hz), 8.26 (1H, d, J=8 Hz), 10.58 (1H,s), 10.88 (1H, br s).

Example 55-[4-(2-Methylbenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (16mg, 0,050 mmol) obtained in Example 1, (3), and 2-methylbenzoyl chloride(16 mg, 0.100 mmol), the title compound (13 mg, yield 59%) was obtainedas off white crystals in the same manner as that of Example 1, (4).

¹H NMR (CDCl₃, 400 MHz) δ: 2.94 (3H, s), 3.60 (2H, 5), 7.06 (1H, d, J=9Hz), 7.2-7.3 (3H, m), 7.36 (1H, t, J=7 Hz), 7.47 (1H, d, J=7 Hz),7.6-7.8 (6H, m), 7.86 (1H, d, J=8 Hz), 8.09 (1H, d, J=8 Hz), 8.52 (1H,s).

Example 65-[4-(2,6-Dimethylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30mg, 0.095 mmol) obtained in Example 1, (3), and 2,6-dimethylbenzoylchloride (0.143 mmol), the title compound (12 mg, yield 18%) wasobtained in the same manner as that of Example 1, (4).

¹H NMR (CDCl₃, 400 MHz) δ: 2.34 (611, 5), 3.55 (1H, d, J=12 Hz), 3.59(1H, d, J=12 Hz), 7.01 (2H, d, J=8 Hz), 7.07 (1H, d, J=9 Hz), 7.16 (1H,t, J=7 Hz), 7.2-7.3 (2H, m), 7.5-7.8 (6H, m), 7.85 (1H, d, J=8 Hz), 8.16(1E, d., J=9 Hz), 9.23 (1H, s).

Example 75-[4-(2,6-Dichlorobenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (20mg, 0.063 mmol) obtained in Example 1, (3), and 2,6-dichlorobenzoylchloride (20 mg, 0.095 mmol), the title compound (20 mg, yield 64%) wasobtained as pale yellow crystals in the same manner as that of Example1, (4).

¹H NMR (CDCl₃, 400 MHz) δ: 3.56 (1H, d, J=12 Hz), 3.59 (1H, d, J=12 Hz),5.9-6.1 (1H, br), 7.06 (1H, d, 7.2-7.4 (5H, m), 7.5-7.7 (5H, m), 7.86(1H, d, J=8 Hz), 8.08 (1H, d, J=8 Hz), 8.57 (1H, s).

Example 85-[4-(3-Chlorobenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (20mg, 0.063 mmol) obtained in Example 1, (3), and 3-chlorobenzoyl chloride(17 mg; 0.095 mmol), the title compound (15 mg, yield 52%) was obtainedas pale yellow crystals in the same manner as that of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=1.2 Hz), 3.71 (1H, d, d=12Hz), 7.01 (1H, d, J=9 Hz), 7.22 (2H, d, J=9 Hz), 7.56 (1H, d, J=8 Hz),7.5-7.7 (4H, m), 7.84 (2H, d, J=8 Hz), 7.91 (2H, d, J=9 Hz), 8.00 (1H,s), 8.25 (1H, d, J=9 Hz), 10.46 (1H, s), 10.89 (1H, br s).

Example 95-[4-(2-Phenylacetylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30mg, 0.095 mmol) obtained in Example 1, (3), and phenylacetyl chloride(40 μL, 0.303 mmol), the title compound (15 mg, yield 36%) was obtainedin the same manner as that of Example 1.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.14 (1H, d, J=12 Hz), 3.65 (2H, s), 3.68(1H, J=12 Hz), 6.97 (1H, d, J=9 Hz), 7.16 (2H, d, J=9 Hz), 7.2-7.4 (6H,m), 7.5-7.7 (4H, m), 7.91 (1H, d, J=8 Hz), 8.25 (1H, d, J=8117), 10.31(1H, s), 10.87 (1H, s).

Example 101-[4-(2,4-Dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-3phenylthiourea

5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (190mg, 0.6 mmol) obtained in Example 1, (3), phenyl isothiocyanate (243 mg,1.8 mmol), and tetrahydrofuran (76 mL) were mixed, and the mixture wasrefluxed by heating for 24 hours. After the mixture was left to cool toroom temperature, the insoluble matter was removed by filtration, andthe filtrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (methanol/chloroform=1/50)to obtain the title compound (114 mg, yield 42%) as slightly yellowcrystals.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d., J=12 Hz), 3.78 (1H, d, J=12Hz), 7.01 (1H, d, J=9 Hz), 7.1-7.2 (3H, m), 7.3-7.4 (2H, m), 7.4-7.6(2H, m), 7.5-7.7 (5H, m), 7.92 (1H, d, J=8 Hz), 8.26 (1H, d, J=8 Hz),9.89 (2H, 8), 10.90 (1H, s).

Example 115-[4-(2,3-Dimethoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (100mg, 0.315 mmol) obtained in Example 1, (3), and 2,3-dimethoxybenzoylchloride (0.473 mmol), the title compound (83 mg, yield 55%) wasobtained in the same manner as that of Example 1, (4).

¹H NMR (CDCl₃, 400 MHz) δ: 3.62 (2H, s), 3.93 (3H, s), 3.99 (3H, s),7.0-7.2 (2H, m), 7.21 (1H, t, J=8 Hz), 7.2-7.3 (2H, m), 7.5-7.6 (2H, m),7.69 (1H, t, J=7 Hz), 7.7-7.8 (3H, m), 7.84 (1H, d, J=8 Hz), 8.15 (1H,d, J=8 Hz), 9.17 (1H, br s), 10.10 (1H, br s).

Example 125-[4-(2-Methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (100mg, 0.315 mmol) obtained in Example 1, (3), and 2-methoxybenzoylchloride (63 μL, 0.473 mmol), the title compound (65 mg, yield 46%) wasobtained in the same manner as that of Example 1, (4).

¹H NMR (CDCl₃, 400 MHz) δ: 3.61 (2H, s), 4.05 (3H, s), 7.02 (1H, d, J=8Hz), 7.05 (1H, d, J=9 Hz), 7.11 (1H, t, J=7 Hz), 7.24 (2H, d, J=9 Hz),7.4-7.5 (1H, m), 7.5-7.6 (2H, m), 7.6-7.8 (3H, m), 7.84 (1H, d, J=8 Hz),8.15 (1H, d, J=8 Hz), 8.24 (1H, dd, J=1 Hz, 8 Hz), 9.1-9.3 (1H, m), 9.85(1H, Jar s).

Example 135-[4-[(2-Chlorophenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,6H)-dione

2-Chlorophenylacetic acid (51 mg, 0.3 mmol) was dissolved in ethylacetate (1.5 mL), the solution was added with thionyl chloride (26 μL,0.36 mmol), and the mixture was refluxed by heating for 4 hours. Thesolvent was evaporated under reduced pressure to give2-chlorophenylacetyl chloride. By using this compound and5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (190mg, 0.6 mmol) obtained in Example 1, (3), the title compound (10 mg,yield 11%) was obtained as pale yellow crystals in the same manner asthat of Example 1, (4).

¹H NMR (DMSO-dc, 400 MHz) δ: 3.14 (1H, d, J=12 Hz), 3.69 (1H, d, J=12Hz), 3.85 (2H, s), 7.00 (1H, d, J=9 Hz), 7.17 (2H, d, J=8 Hz), 7.3-7.4(2H, m), 7.4-7.5 (2H, m), 7.5-7.7 (5H, m), 7.91 (1H, d, J=8 Hz), 8.25(1H, d, J=9 Hz), 10.36 (1H, s), 10.88 (1H, s).

5-[4-(2,3-Dimethylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30mg, 0.095 mmol) obtained in Example 1, (3), and 2,3-dimethylbenzoylchloride (0.143 mmol), the title compound (4.5 mg, yield 11%) wasobtained in the same manner as that of Example 1, (4).

¹H NMR (CDCl₃, 400 MHz) δ: 2.31 (3H, s), 2.37 (3H, s), 3.58 (2H, s),7.06 (1H, d, J=9 Hz), 7.14 (1H, d, J=7 Hz), 7.2-7.3 (4H, m), 7.42 (1H,br s), 7.5-7.7 (5H, m), 7.84 (1H, d, J=8 Hz), 8.05 (1H, d, J=8 Hz), 8.23(1H, br s).

Example 155-[4-(2,5-Dimethylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2.4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30mg, 0.095 mmol) obtained in Example 1, (3), and 2,5-dimethylbenzoylchloride (0.143 mmol), the title compound (14 mg, yield 33%) wasobtained in the same manner as that of Example 1, (4).

¹H NMR (CDCl₃, 400 MHz) δ: 2.33 (3H, s), 2.42 (3H, s), 3.59 (2H, s),7.05 (1H, d, J=9 Hz), 7.12 (1H, d, J=8 Hz), 7.15 (1H, d, J=8 Hz),7.2-7.3 (3H, m), 7.5-7.8 (6H, m), 7.85 (1H, d, J=8 Hz), 8.13 (1H, d,J=9H2), 9.00 (1H, br s).

Example 165-[4-(5-Bromo-2-chlorobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (20mg, 0.063 mmol) obtained in Example 1, (3), and 5-bromo-2-chlorobenzoylchloride (0.0945 mmol), the title compound (8 mg, yield 24%) wasobtained as pale yellow crystals in the same manner as that of Example1, (4).

¹H NMR (CDCl₃, 400 MHz) δ: 3.61 (2H, s), 7.05 (1H, d, J=9 Hz), 7.28 (1H,d, J=9 Hz), 7.33 (1H, d, J=9 Hz), 7.55 (1H, dd, J=2 Hz, 9 Hz), 7.6-7.8(6H, m), 7.8-7.9 (3H, m), 8.04 (1H, d, J=9 Hz), 8.11 (1H, s).

5-[4-(2,4-Dichlorobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (25mg, 0.078 mmol) obtained in Example 1, (3), and 2,4-dichlorobenzoylchloride (25 mg, 0.118 mmol), the title compound (20 mg, yield 52%) wasobtained as white crystals in the same manner as that of Example 1, (4).

¹H NMR (CDCl₃, 400 MHz) δ: 3.60 (2H, s), 7.00 (1H, d, J=8 Hz), 7.26 (2H,d, 7.37 (1H, dd, J=2 Hz, 8 Hz), 7.48 (1H, (I, J=2 Hz), 7.5-7.8 (6H, m),7.87 (1H, d, J=8 Hz), 7.99 (1H, s), 8.06 (1H, d, J=8 Hz), 8.31 (1H, brs).

Example 185-[4-(2-Hydroxybenzoylamino)phenyl]-1H-naphtho[1,4]diazepine-2,4(3H,5H)-dione

5-[4-(2-Methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(56 mg, 0.124 mmol) obtained in Example 12 was dissolved indichloromethane (1.2 mL), the solution was added with a 1 M solution ofboron tribromide in dichloromethane (0.37 mL, 0.37 mmol) on an ice bath,and the mixture was stirred at room temperature for 16 hours. Aftercompletion of the reaction, the reaction mixture was added with 25%aqueous ammonia, and the mixture was extracted with chloroform. Then,the organic layer was dried over sodium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (chloroform/methanol=100/1) to give thetitle compound (39 mg, yield 72%).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.16 (1H, d, J=12 Hz), 3.70 (1H, d, J=12Hz), 6.89 (1H, t, J=7 Hz), 6.94 (1H, d, J=8 Hz), 7.02 (1H, d, J=91-12),7.22 (2H, d, J=9 Hz), 7.39 (1H, t, J=8 Hz), 7.59 (1H, t, J=8 Hz), 7.65(1H, d, J=8 Hz), 7.70 (1H, d, J=9 Hz), 7.78 (2H, d, J=9 Hz), 7.92 (2H,d, J=8 Hz), 8.25 (1H, d., J-=9 Hz), 10.89 (2H, br s).

Example 195-[4-(2,3-Dihydroxybenzoylamino)phenyl]-1H-naphtho[1,2b][1,4]diazepine-2,4(3H,5H)-dione

By using5-[4-(2,3-dimethoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(71 mg, 0.147 mmol) obtained in Example 11, the title compound (4.9 mg,yield 7%) was obtained in the same manner as that of Example 18.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.71 (1H, d, J=12Hz), 6.6-6.8 (1H, m), 6.9-7.0 (1H, m), 7.01 (1H, d, J=9 Hz), 7.22 (2H,d, J=9 Hz), 7.39 (1H, d, J=9 Hz), 7.59 (1H, t, J=8 Hz), 7.65 (1H, d, J=8Hz), 7.70 (1H, d, J=9 Hz), 7.76 (2H, d, J=9 Hz), 7.91 (1H, d, J=8 Hz),8.25 (1H, d, J=8 Hz), 10.89 (1H, s).

Example 201-[4-(2,4-Dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-3-phenylurea

A suspension of5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32mg, 0.10 mmol) obtained in Example 1, (3) in anhydrous tetrahydrofuran(10 mL) was added with phenyl isocyanate (27 μL, 0.25 mmol), the mixturewas refluxed by heating at 65° C. for 4 hours. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (chloroform/methanol=50/1) to obtainthe title compound (9 mg, yield 21%) as white powder.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.69 (1H, d, J=12Hz), 6.97 (1H, t, J=8 Hz), 7.02 (1H, d, J=9 Hz), 7.14 (2H, d, J=9 Hz),7.28 (2H, t, J=8 Hz), 7.45 (2H, d, J=8 Hz), 7.52 (2H, d, J=9 Hz), 7.59(1H, t, J=8 Hz), 7.6-7.7 (2H, m), 7.91 (1H, d, J=8 Hz), 8.25 (1H, d, J=8Hz), 8.68 (1H, s), 8.81 (1H, s), 10.86 (1H, s).

Example 215-[4-[(2,6-Dichlorophenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

2,6-Dichlorophenylacetic acid (62 mg, 0.3 mmol) was treated with thionylchloride in the same manner as that of Example 13, and then by using theresultant together with5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (63mg, 0.2 mmol) obtained in Example 1, (3), the title compound (32 mg,yield 32%) was obtained as pale brown crystals in the same manner asthat of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.69 (1H, d, J=12Hz), 4.07 (2H, s), 7.00 (1H, d, J=9 Hz), 7.17 (2H, d, J=8 Hz), 7.34 (1H,t, J=8 Hz), 7.49 (2H, d, J=8 Hz), 7.5-7.7 (5H, m), 7.92 (1H, d, J=8 Hz),8.25 (1H, d, J=9 Hz), 10.45 (1H, s), 10.88 (1H, s).

Example 225-[4-[(2-Methoxyphenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

2-Methoxyphenylacetic acid (75 mg, 0.45 mmol) was treated with thionylchloride in the same manner as that of Example 13, and then by using theresultant together with5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (95mg, 0.3 mmol) obtained in Example 1, (3), the title compound (83 mg,yield 60%) was obtained as pale yellow crystals in the same manner asthat of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.14 (1H, d, J=1.2 Hz), 3.64 (2H, s), 3.69(1H, d, J=12 Hz), 3.77 (3H, s), 6.90 (1H, t, J=7 Hz), 6.9-7.0 (2H, m),7.15 (2H, d, J=8 Hz), 7.2-7.3 (2H, m), 7.59 (1H, t, J=8 Hz), 7.6-7.7(4H, m), 7.91 (1H, d, J=8 Hz), 8.25 (1H, d, J=8 Hz), 10.17 (1H, s),10.86 (1H, s).

Example 235-[4-[(2-Hydroxyphenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

5-[4-[(2-Methoxyphenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(50 mg, 0.11 mmol) obtained in Example 22 was dissolved in drydichloromethane (20 the solution was added with a 1 M solution of borontribromide in dichloromethane (0.22 mi.), and the mixture was stirred atroom temperature for 24 hours. The solvent was evaporated, the residuewas added with saturated aqueous sodium hydrogencarbonate, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure, and the residue waswashed with ethyl acetate to give the title compound (14 mg, yield 28%)as pale yellow crystals.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.14 (1H, d, J=12 Hz), 3.61 (2H, s), 3.69(1H, d, J=12 Hz), 6.7-6.9 (2H, m), 6.9-7.2 (3H, m), 7.16 (2H, d, J=7Hz), 7.4-7.7 (3H, m), 7.67 (2H, d, J=7 Hz), 7.91 (1H, d, J=7 Hz), 8.25(1H, d, J=8. Hz), 9.48 (1H, s), 10.19 (1H, s), 10.88 (1H, s).

1-(2-Chlorophenyl)-3-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]thiourea

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (190mg, 0.60 mmol) obtained in Example 1, (3), and 2-chlorophenylisothiocyanate (196 μL, 1.50 mmol), the title compound (127 mg, yield44%) was obtained in the same manner as that of Example 20.

¹H NMR (CDCl₃, 400 MHz) δ: 3.61 (2H, s), 7.01 (1H, d, J=9 Hz), 7.19 (1H,t, J=8 Hz), 7.2-7.4 (3H, m), 7.4-7.5 (3H, m), 7.5-7.7 (2H, m), 7.69 (1H,t, J=8 Hz), 7.86 (1H, d, J=8 Hz), 7.9-8.0 (2H, m), 8.08 (1H, br s), 8.12(1H, d, J=9 Hz), 8.89 (1H, br s).

Example 255-[4-[3-(Trifluoromethyl)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30mg, 0.095 mmol) obtained in Example 1, (3), and3-(trifluoromethyl)benzoyl chloride (17 μL, 0.114 mmol), the titlecompound (6 mg, yield 13%) was obtained in the same manner as that ofExample 1, (4).

¹H NMR (CDCl₃, 400 MHz) δ: 3.58 (1H, d, J=12 Hz), 3.61 (1H, d, J=12 Hz),7.01 (1H, d, J=9 Hz), 7.13 (2H, d, J=814z), 7.5-7.7 (6H, m), 7.79 (1H,d, J=8 Hz), 7.83 (1H, d, J=8 Hz), 8.10 (2H, t, J=8 Hz), 8.18 (1H, s),8.40 (1H, br s), 8.86 (1H, br s),

Example 265-[4-[2[(2-Trifluoromethyl)phenyl]acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30mg, 0.095 mmol) obtained in Example 1, (3), and2-(trifluoromethyl)phenylacetyl chloride (29 μL, 0.143 mmol), the titlecompound (6 mg, yield 13%) was obtained in the same manner as that ofExample 1, (4).

¹H NMR (CDCl₃, 400 MHz) δ: 3.58 (2H, s), 3.89 (2H, s), 6.99 (1H, d, J=9Hz), 7.16 (2H, d, J=8 Hz), 7.30 (1H, br s), 7.4-7.6 (7H, m), 7.66 (1H,d, J=8 Hz), 7.71 (1H, d, 7.84 (1H, d, J=8 Hz), 8.06 (1H, t, J=8 Hz),8.54 (1H, br s).

Example 271-(2-Chlorophenyl)-3-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]urea

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32mg, 0.10 mmol) obtained in Example 1, (3), and 2-chlorophenyl isocyanate(30 μL, 0.25 mmol), the title compound (19 mg, yield 40%) was obtainedin the same manner as that of Example 20.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=11 Hz), 3.69 (1H, d, J=12Hz), 7.0-7.1 (2H, m), 7.16 (2H, d, J=9 Hz), 7.30 (1H, t, J=8 Hz),7.4-7.8 (6H, m), 7.92 (1H, d, J=8 Hz), 8.16 (1H, d, J=8 Hz), 8.25 (1H,d, J=8 Hz), 8.34 (1H, s), 9.58 (1H, s), 10.89 (1H, s).

Example 285-[4-[(2-Phenylpropionyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

2-Phenylpropionic acid (30 mg, 0.2 mmol) was treated with thionylchloride in the same manner as that of Example 13, and then by using theresultant together with5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32mg, 0.1 mmol) obtained in Example 1, (3), the title compound (10 mg,yield 22%) was obtained as pale brown crystals in the same manner asthat of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 1.42 (3H, d, J=7 Hz), 3.13 (1H, d, J=12Hz), 3.68 (1H, d, J=12 Hz), 3.84 (1H, q, J=7 Hz), 6.96 (1H, d, J=9 Hz),7.14 (2H, d, J=9 Hz), 7.2-7.4 (5H, m), 7.5-7.7 (5H, m), 7.90 (1H, d, J=8Hz), 8.24 (1H, d, J=8 Hz), 10.19 (1H, s), 10.87 (1H, s).

Example 295-[4-(2-Chloro-3-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dime

By using obtained in5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (150mg, 0.47 mmol) Example 1, (3), and 2-chloro-3-methoxybenzoyl chloride(0.71 mmol), the title compound (119 mg, yield 52%) was obtained in thesame manner as that of Example 1, (4).

¹H NMR (DMSO-dr, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.71 (1H, d, J=12Hz), 3.90 (3H, s), 7.01 (1H, d, J=9 Hz), 7.12 (1H, d, J=8 Hz), 7.20 (2H,d, J=7 Hz), 7.26 (1H, d, J=9 Hz), 7.42 (1H, t, 7.59 (1H, t, J=8 Hz),7.6-7.7 (2H, m), 7_76 (2H, d, J=7 Hz), 7.92 (1H, d, J=8 Hz), 8.25 (1H,d, J=8 Hz), 10.61 (I H, s), 10.89 (1H, s).

Example 305-[4-(3-Phenylpropionylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (50mg, 0.16 mmol) obtained in Example 1, (3), and 3-phenylpropionylchloride (28 μL, 0.19 mina, the title compound (21 mg, yield 29%) wasobtained in the same manner as that of Example 1, (4).

¹H NMR (CDCl₃, 400 MHz) δ: 2.64 (2H, t, J=7 Hz), 3.02 (2H, t, J=7 Hz),3.57 (2H, s), 6.98 (1H, d, J=9 Hz), 7.05 (2H, d, J=8 Hz), 7.1-7.3 (5H,m), 7.38 (2H, d, J=8 Hz), 7.5-7.6 (3H, m), 7.68 (1H, t, J=8 Hz), 7.83(1B, d, J=0.8 Hz), 8.13 (11f, d, J=8 Hz), 9.14 (1H, br s).

Example 315-[4-[(1H-Indole-3-carbonyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

Indole-3-carboxylic acid (51 mg, 0.316 mmol) was made into acid chloridein a conventional manner. By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (50mg, 0.158 mmol) obtained in Example 1, (3), and indole-3-carboxylic acidchloride mentioned above, the title compound (40 mg, yield 55%) wasobtained in the same manner as that of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.16 (1H, d, J=12 Hz), 3.70 (1H, d, J=12Hz), 7.05 (1H, d, J=9 Hz), 7.1-7.2 (4H, m), 7.47 (1H, d, J=7 Hz), 7.59(1H, t, J=8 Hz), 7.6-7.7 (2H, m), 7.85 (2H, d, J=9 Hz), 7.92 (1H, d, J=8Hz), 8.19 (1H, d, J=8 Hz), 8.2-8.3 (2H, m), 9.84 (1H, s), 10.89 (1H, brs), 11.73 (1H, br s).

Example 325-[4-(2-Chloro-3-hydroxybenzoylamino)phenyl]-1H-naohtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-[4-(2-chloro-3-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 29, the title compound (53 mg, yield 56%) wasobtained in the same manner as that of Example 18.

¹H NMR (DMSO-c16, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.70 (1H, d, J=12Hz), 6.96 (1H, d, J=8 Hz), 7.01 (1H, d, J=9 Hz), 7.06 (1H, d, J=8 Hz),7.1-7.3 (3H, m), 7.59 (1H, t, J=8 Hz), 7.65 (1H, d, J=8 Hz), 7.69 (1H,d, J=8 Hz), 7.77 (2H, d, J=8 Hz), 7.91 (1H, d, J=8 Hz), 8.24 (1H, d, J=9Hz), 10.42 (1H, s), 10.56 (1H, s), 10.88 (1H, s).

Example 335-[4-[(2-Methyl-2-phenylpropionyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

2-Methyl-2-phenylpropionic acid (33 mg, 0.2 mmol) was treated withthionyl chloride in the same manner as that of Example 13, and then byusing the resultant together with5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32mg, 0.1 mmol) obtained in Example 1, (3), the title compound (23 mg,yield 50%) was obtained as slightly brown powder in the same manner asthat of Example 1, (4).

¹H NMR (DMSO-de, 400 MHz) δ: 1.57 (6H, s), 3.14 (1H, d, J=12 Hz), 3.68(1H, d, J=12 Hz), 6.98 (1H, d, J=9 Hz), 7.13 (2H, d, J=8 Hz), 7.2-7.3(1H, m), 7.3-7.4 (4H, m), (5H, m), 7.91 (1H, d, J=7 Hz), 8.24 (1H, d,J=8 Hz), 9.23 (1H, s), 10.86 (1H, s).

Example 345-[4-(2-Phenoxyacetylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (50mg, 0.157 mmol) obtained in Example 1, (3), and 2-phenoxyacetyl chloride(27 mg, 0.315 mmol), the title compound (13 mg, yield 18%) was obtainedas pale brown crystals in the same manner as that of Example 1, (4).

¹H NMR (CDCl₃, 400 MHz) δ: 3.60 (2H, s), 4.62 (2H, s), 6.9-7.1 (4H, m),7.2-7.3 (2H, m), 7.3-7.4 (2H, m), 7.5-7.7 (5H, m), 7.86 (1H, d, J=8 Hz),8.05 (1H, d, J=8 Hz), 8.25 (1H, br s), 8.33 (1H, s).

Example 355-[4-[2-(2-Chloro-4-methoxyphenyl)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (50mg, 0.158 mmol) obtained in Example 1, (3), and2-chloro-4-methoxyphenylacetyl chloride (0.237 mmol), the title compound(76 mg, yield 48%) was obtained in the same manner as that of Example 1,(4).

¹H NMR (CDCl₃, 400 MHz) δ: 3.58 (2H, s), 3.78 (2H, s), 3.81 (3H, s),6.84 (1H, dd, J=2 Hz, 9 Hz), 6.9-7.0 (2H, m), 7.16 (2H, d, J=8 Hz), 7.29(1H, d, J=8 Hz), 7.34 (1H, br s), 7.49 (2H, d, J=8 Hz), 7.5-7.6 (2H, m),7.68 (1H, t, J=8 Hz), 7.84 (1H, d, J=8 Hz), 8.08 (1H, d, J=8 Hz), 8.68(1H, br s).

Example 365-[4-[(1-Methyl-1H-imidazole-2-carbonyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

1-Methyl-1H-imidazole-2-carboxylic acid (40 mg, 0.317 mmol) was madeinto acid chloride in a conventional manner. By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (50mg, 0.158 mmol) obtained in Example 1, (3), and1-methyl-1H-imidazole-2-carboxylic acid chloride mentioned above, thetitle compound (9 mg, yield 13%) was obtained in the same manner as thatof Example 1.

¹H NMR (CDCl₃, 400 MHz) δ: 3.60 (2H, s), 4.11 (3H, s), 7.0-7.1 (3H, m),7.2-7.3 (2H, m), 7.5-7.7 (2H, m), 7.6-7.8 (3H, m), 7.86 (1H, d, J=8 Hz),8.06 (1H, d, J=9 Hz), 8.38 (1H, s), 9.33 (1H, s).

Example 375-[4-[2-(2,4-Dichlorophenyl)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

2,4-Dichlorophenylacetic acid (65 mg, 0.317 mmol) was made into acidchloride in a conventional manner. By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (50mg, 0.158 mmol) obtained in Example 1, (3), and 2,4-dichlorophenylaceticacid chloride mentioned above, the title compound (27 mg, yield 34%) wasobtained in the same manner as that of Example 1.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.14 (1H, d, J=12 Hz), 3.69 (1H, d, J=12Hz), 3.85 (2H, a), 6.99 (1H, d, J=9 Hz), 7.17 (2H, d, J=9 Hz), 7.3-7.5(2H, m), 7.5-7.7 (OH, m), 7.91 (1H, d, J=8 Hz), 8.25 (1H, d, J=8 Hz),10.38 (1H, s), 10.88 (1H, s).

Example 385-[4-[2-(2-Chloro-4-hydroxyphenyl)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-[4-[2-(2-chloro-4-methoxyphenyl)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(40 mg, 0.08 mmol) obtained in Example 35, the title compound (10 mg,yield 26%) was obtained in the same manner as that of Example 18.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.13 (1H, d, J=12 Hz), 3.6-3.7 (3H, m),6.70 (1H, d, J=9 Hz), 6.81 (1H, s), 6.98 (1H, d, J=9 Hz), 7.15 (2H, d,J=8 Hz), 7.19 (1H, d, J=8 Hz), 7.5-7.7 (5H, m), 7.90 (1H, d, J=7 Hz),8.23 (1H, d, J=9 Hz), 9.75 (1H, s), 10.26 (1H, s), 10.87 (1H, s).

Example 395-[4-(3-Phenylpropenylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (50mg, 0.158 mmol) obtained in Example 1, (3), and cinnamoyl chloride (32mg, 0.19 mmol), the title compound (622 mg, yield 31%) was obtained inthe same manner as that of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.70 (1H, d, J=12Hz), 6.83 (1H, J=16 Hz), 7.00 (1H, d, J=9 Hz), 7.19 (2H, d, J=9 Hz),7.3-7.5 (3H, m), 7.5-7.7 (6H, m), 7.76 (2H, d, J=9 Hz), 7.91 (1H, d, J=8Hz), 8.25 (1H, d, J=9 Hz), 10.35 (1H, s), 10.89 (1H, br s).

Example 405-[4-[(3-Pyridylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2.4(3H,5H)-dione hydrochloride (1)5-[4-[(3-Pyridylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

3-Pyridylacetic acid (41 mg, 0.3 mmol) was dissolved in drydichloromethane (1 mL), the solution was added with dimethylformamide (1drop), and oxalyl chloride (0.03 mL, 0.36 mmol), and the mixture wasstirred at room temperature for 1 hour. The solvent was evaporated underreduced pressure to give 3-pyridylacetyl chloride hydrochloride. Byusing this compound and5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (63mg, 0.2 mmol) obtained in Example 1, (3), the title compound (6.2 mg,yield 7%) was obtained as yellow amorphous in the same manner as that ofExample 1, (4).

¹H NMR (CDCl₃, 400 MHz) δ: 3.5-3.7 (4H, m), 6.9-7.1 (3H, m), 7.2-7.3(1H, m), 7.38 (2H, d, J=8 Hz), 7.5-7.6 (2H, m), 7.66 (1H, t, J=7 Hz),7.73 (1H, d, J=7 Hz), 7.80 (1H, d, J=8 Hz), 8.17 (1H, d, J=9 Hz), 8.47(1H, s), 8.5-8.7 (2H, m), 9.57 (1H, s).

(2)5-[4-[(3-Pyridylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dionehydrochloride

5-[4-[(3-Pyridylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(6.2 mg, 0.014 mmol) was dissolved in chloroform (6 mL), the solutionwas added with a 4M solution of hydrogen chloride in ethyl acetate (0.01mL), and the solvent was evaporated under reduced pressure. The residuewas concentrated from ethyl acetate under reduced pressure, and thenwashed with ethyl acetate to obtain the title compound (4.8 mg, yield71%) as pale brown powder.

¹H NMR (DMSO-c1.6, 400 MHz) δ; 3.14 (1H, d, J=12 Hz), 3.69 (1H, d, J=12Hz), 3.89 (2H, s), 6.97 (1H, d, J=9 Hz), 7.18 (2H, d, J=9 Hz), 7.5-7.8(6H, m), 7.91 (1H, d, J=8 Hz), 8.18 (1H, d, J=7 Hz), 8.25 (1H, d, J=9Hz), 8.67 (1H, d, J=5 Hz), 8.73 (1H, s), 10.47 (1H, s), 10.88 (1H, s).

Example 415-[4-(1H-Benzimidazole-2-carbonylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

1H-Benzimidazole-2-carboxylic acid monohydrate (14 mg, 0.077 mmol),5-(4-aminophenyl)-1H-naphtho[1,2-h][1,4]diazepine-2,4(3H,5H)-dione (23mg, 0.072 mind) obtained in Example 1, (3), dimethylformamide (1.4 mL),and 1-hydroxybenzotriazole monohydrate (ii mg, 0.08 mmol) were mixed,and the mixture was stirred at room temperature for 3 hours. Thisreaction mixture was added with water, and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with saturatedaqueous sodium hydrogencarbonate, and then with saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography (hexane/ethyl acetate=4/1), and then recrystallized fromethyl acetate/hexane to give the title compound (15 mg, yield 43%) asslightly yellow crystals,

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.16 (1H, d, J=12 Hz), 3.71 (1H, d, J=12Hz), 7.03 (1H, d, J=9 Hz), 7.24 (2H, d, J=9 Hz), 7.3-7.4 (2H, m),7.5-7.8 (5H, m), 7.92 (1H, d, J=8 Hz), 7.98 (2H, d, J=9 Hz), 8.26 (1H,d, J-=8 Hz), 10.90 (1H, s), 11.04 (1H, s), 13.42 (1H, br s).

1-[4-(2,3-Dimethylbenzoylamino)phenyl]-7-methoxy-1H-1,5-benzodiazepine-2,4(3H,5H)-dione(1) tert-Butyl4-(7-methoxy-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)phenylcarbamate

tert-Butyl 4-(2-amino-4-methoxyphenylamino)phenylcarbamate (500 mg, 1.52mmol) synthesized in the same manner as that of Example 1 by using4-methoxy-2-nitrophenol as the starting material was dissolved inanhydrous tetrahydrofuran (30 mL), and the solution was added dropwisewith malonyl chloride (0.178 mL, 1.82 mmol) on an ice bath. The mixturewas stirred at room temperature for 16 hours. After completion of thereaction, the reaction mixture was added with saturated aqueous sodiumhydrogencarbonate, the aqueous layer was extracted with chloroform, theorganic layer was dried over sodium sulfate, and then the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (chloroform/methanol=100/1) to give thetitle compound (230 mg, yield 38%).

¹H NMR (CDCl₃, 400 MHz) δ: 1.51 (9H, s), 3.53 (2H, s), 3.80 (3H, s),6.6-6.7 (3H, m), 6.83 (1H, d, J=9 Hz), 7.11 (2H, d, J=9 Hz), 7.37 (2H,d, J=9 Hz), 9.24 (1H, s).

(2) 1-(4-Aminephenyl)-7-methoxy-1H-1,5-benzodiazepine-2,4(3H,5H)-dione

By using tert-butyl4-(7-methoxy-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)phenylcarbamate(230 mg, 0.58 mmol) obtained above as the starting material, the titlecompound (125 mg, yield 72%) was obtained in the same manner as that ofExample 1.

¹H NMR (DMSO-d₆, 400 MHz) δ; 3.03 (1H, br s), 3.53 (1H, br s), 3.72 (3H,s), 5.19 (2H, s), 6.53 (2H, d, J=9 Hz), 6.6-6.7 (2H, m), 6.74 (2H, d,J=9 Hz), 6.80 (1H, d, J=8 Hz), 10.4 (1H, s).

(3)1-[4-(2,3-Dimethylbenzoylamino)phenyl]-7-methoxy-1H-1,5-benzodiazepine-2,4(3H,5H)-dione

By using1-(4-aminophenyl)-7-methoxy-1H-1,5-benzodiazepine-2,4(3H,5H)-dione (60mg, 0.4 mmol) obtained above, and 2,3-dimethylbenzoyl chloride (0.6mmol), the title compound (23 mg, yield 13%) was obtained in the samemanner as that of Example 1, (4).

¹H NMR (CDCl₃, 400 MHz) δ: 2.31 (3H, s), 2.36 (3H, s), 3.53 (2H, s),3.81 (3H, s), 6.62 (1H, d, J=3 Hz), 6.68 (1H, dd, J=2 Hz, 9 Hz), 6.88(1H, d, J=9 Hz), 7.1-7.3 (5H, m), 7.55 (1H, s), 7.65 (2H, d, J=9 Hz),8.17 (1H, s).

Example 435-[4-[(Benzoylamino)methyl]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(1) tert-Butyl 4-(1-aminonaphthalen-2 ylamino)benzylcarbamate

By using tert-butyl 4-(1-nitronaphthalen-2-ylamino)benzylcarbamate, thetitle compound was obtained in the same manner as that of Example 1,(2).

¹H NMR (CDCl₃, 400 MHz) δ: 1.45 (9H, s), 4.20 (2H, s), 6.74 (2H, d, J=9Hz), 7.12 (2H, d, J=8 Hz), 7.32 (2H, d, J=8 Hz), 7.4-7.6 (3H, m), 7.81(1H, d, J=8 Hz), 7.87 (1H, d, J=8 Hz).

(2) tert-Butyl4-[2,4-dioxo-3,4-dihydro-1H-naphtho[2,1-b][1,4]diazepin-5(2H)-yl]benzylcarbamate

By using tert-butyl 4-(1-aminonaphthalen-2-ylamino)benzylcarbamate, thetitle compound was obtained in the same manner as that of Example 42,(1).

1H NMR (CDCl₃, 400 MHz) δ: 1.46 (9H, s), 3.60 (2H, s), 4.34 (2H, s),4.89 (1H, br s), 7.01 (1H, d, J=9 Hz), 7.22 (2H, d. J=8 Hz), 7.33 (2H,d, J=8 Hz), (2H, m), 7.69 (1H, t, J=8 Hz), 7.84 (1H, d, J=8 Hz), 8.09(1H, d, J=9 Hz), 8.70 (1H, br s).

(3)5-[4-(Aminomethyl)phenyl]-1H-naphtho[2,1-b][1,4]diazepine-2,4(3H,5H)-dione

By using Cert-butyl4-[2,4-dioxo-3,4-dihydro-1H-naphtho[2,1-b][1,4]diazepin-5(2H)-yl]benzylcarbamate,the title compound was obtained in the same manner as that of Example 1,(3).

¹H NMR (CDCl₃, 400 MHz) δ: 3.61 (2H, s), 3.91 (2H, s), 7.03 (1H, d, J=9Hz), 7.2-7.3 (2H, m), 7.38 (2H, d., J=8 Hz), 7.59 (1H, d, J=9 Hz), 7.60(1H, t, J=7 Hz), 7.69 (1H, t, J=7 Hz), 7.85 (1H, d, J=8 Hz), 8.06 (1H,d, J-=9 Hz), 8.32 (1H, br s).

(4)5-[4-[(Benzoylamino)methyl]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-[4-(aminomethyl)phenyl]-1H-naphtho[2,1-b][1,4]diazepine-2,4(3H,5H)-dione,the title compound was obtained in the same manner as that of Example 1,(4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.14 (1H, d, J=12 Hz), 3.70 (1H, d, J=12Hz), 4.51 (2H, d, J=6 Hz), 6.97 (1H, d, J=9 Hz), 7.18 (2H, el, J=8 Hz),7.39 (2H, d, J=8 Hz), 7.4-7.7 (6H, m), 7.89 (311, 4, J=8 Hz), 8.24 (1H,d, J=8 Hz), 9.07 (1H, t, J=6 Hz), 10.87 (1H, s).

5-[4-[(2-Chlorobenzoylamino)methyl]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-[4-(aminomethyl)phenyl]-1H-naphtho[2,1-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 43, (3), and 2-chlorobenzoyl chloride, the titlecompound was obtained in the same manner as that of Example 43, (5).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.14 (1H, d, J=12 Hz), 3.70 (1H, d, J=12Hz), 4.48 (2H, d, J=6 Hz), 6.97 (1H, d, J=9 Hz), 7.21 (2H, d, J=8 Hz),7.3-7.7 (9H, m), 7.90 (1H, d, J=8 Hz), 8.25 (1H, d, J=9 Hz), 9.00 (1H,t, J=6 Hz), 10.89 (1H, s).

Example 451-[4-(2,3-Dimethylbenzoylamino)phenyl]-7-hydroxy-1H-1,5-benzodiazepine-2,4(3H,5H)-dione

By using1-[4-(2,3-dimethylbenzoylamino)phenyl]-7-methoxy-1H-1,5-benzodiazepine-2,4(3H,5H)-dione(20 mg, 0.047 mmol) obtained in Example 42, the title compound (7 mg,yield 36%) was obtained in the same manner as that of Example 18.

¹H NMR (DMSO-d₆, 400 MHz) δ: 2.24 (3H, s), 2.28 (3H, s), 3.0-3.1 (1H,m), 3.5-3.7 (1H, m), 6.52 (1H, dd, J=3 Hz, 9 Hz), 6.61 (1H, d, J=2 Hz),6.68 (1H, d, J=9 Hz), 7.09 (2H, d, J=8 Hz), 7.1-7.3 (3H, m), 7.74 (2H,d, J=9 Hz), 9.74 (1H, s), 10.38 (1H, s), 10.42 (1H, s).

Example 465-[4-(2-Chlorobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30mg, 0.095 mmol) obtained in Example 1, (3), and 2-chlorobenzoyl chloride(144, 0.114 mmol), the title compound (13 mg, yield 30%) was obtained inthe same manner as that of Example 1, (4).

¹H NMR (CDCl₃, 400 MHz) δ: 3.59 (2H, s), 7.06 (1H, d, J=9 Hz), 7.2-7.3(2H, m), 7.3-7.5 (3H, m), 7.5-7.7 (5H, m), 7.76 (1H, dd, J=2115, 7 Hz),7.85 (1H, d, J=8 Hz), 7.93 (1H, br s), 8.03 (1H, d, J=8 Hz), 8.07 (1H,s).

Example 475-[4-(2-Bromobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30mg, 0.095 mmol) obtained in Example 1, (3), and 2-bromobenzoyl chloride(0.143 mmol), the title compound (10 mg, yield 21%) was obtained in thesame manner as that of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.70 (1H, d, J=12Hz), 7.02 (1H, d, J=9 Hz), 7.21 (2H, d, J=8 Hz), 7.42 (1H, t, J=7 Hz),7.50 (1H, t, J=7 Hz), 7.56 (1H, J=8 Hz), 7.60 (1H, d, J=8 Hz), 7.6-7.7(3H, m), 7.77 (2H, d, J=8 Hz), 7.92 (1H, d, J=8 Hz), 8.25 (1H, d, J=9Hz), 10.63 (1H, s), 10.88 (1H, br s).

Example 485-[4-(2-Iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-h][1,4]diazepine-2,4(3H,5H)-dione (30mg, 0.095 mmol) obtained in Example 1, (3), and 2-iodobenzoyl chloride(0.143 mmol), the title compound (16 mg, yield 31%) was obtained in thesame manner as that of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.70 (1H, d, J=12Hz), 7.02 (1H, J=9 Hz), 7.1-7.3 (3H, m), 7.4-7.5 (2H, m), 7.59 (1H, t,J=7110, 7.65 (1H, d, J=8 Hz), 7.70 (1H, d, J=9 Hz), 7.77 (2H, d, J=9Hz), 7.92. (2H, t, J=7 Hz), 8.25 (1H, d, J=8 Hz), 10.57 (1H, a), 10.89(1H, e).

Example 495-[4-(2,3-Dimethylbenzoylamino)-3-fluorophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(1) N²-(4-Amino-3-fluorophenyl)naphthalene-1,2-diamine

By using 2-fluoro-4-nitroaniline as the starting material, the titlecompound was obtained in the same manner as that of Example 1.

¹H NMR (CDCl₃, 400 MHz) δ: 1.51 (9H, s), 4.36 (2H, br s), 5.22 (1H, brs), 6.37 (2H, J=2 Hz, 13 Hz), 6.50 (1H, d, J=9 Hz), 7.23 (1H, d, J=9Hz), 7.30 (1H, d, J=9 Hz), 7.4-7.5 (2H, m), 7.73 (1H, br s), 7.81 (2H,m).

(2) 5-[4-(2,3-Dimethylbenzoylamino)-3fluorophenyl]1H-naphtho[1,2b][1,4]diazepine-2,4(3H,5H)-dione

By using N²-(4-amino-3-fluorophenyl)naphthalene-1,2diamine obtainedabove,5-(4-amino-3-fluorophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(20 mg, 0.06 mmol) obtained in the same manner as that of Example 42,(1) and (2), and 2,3-dimethylbenzoyl chloride (0.09 mmol), the titlecompound (18 mg, yield 64%) was obtained in the same manner as that ofExample 1, (4).

¹H NMR (CDCl₃, 400 MHz) δ: 2.33 (3H, s), 2.38 (3H, s), 3.61 (2H, s),7.06 (2H, d, J=9 Hz), 7.1-7.2 (2H, m), 7.2-7.4 (2H, m), 7.6-7.8 (4H, m),7.87 (1H, d, J=8 Hz), 8.16 (1H, d, J=9 Hz), 8.55 (1H, t, J=8 Hz), 9.17(1H, s).

Example 505-[4-[2-(2-Methylphenyl)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using o-tolylacetyl chloride, the title compound was obtained in thesame manner as that of Example 1, (4).

¹H NMR (DMSO-ds 400 MHz) δ: 2.29 (3H, s), 3.13 (1H, d, 3.68 (2H, s),3.68 (1H, d, J=12 Hz), 6.98 (1H, d, J=9 Hz), 7.1-7.3 (6H, m), 7.5-7.7(5H, m), 7.90 (1H, d, J=8 Hz), 8.24 (1H, d, J=9 Hz), 10.28 (1H, s),10.87 (1H, s).

Example 515-[4-[(Quinoxalin-2-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32mg, 0.101 mmol) obtained in Example 1, (3), quinoxaline-2-carboxylicacid (35 mg, 0.202 mmol), andO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(42 mg, 0.111 mmol) were dissolved in DMF (2.0 mL), then the solutionwas added with triethylamine (20 mg, 0.202 mmol), and the mixture wasstirred over night. The reaction mixture was treated in a conventionalmanner to obtain the title compound (10 mg, yield 21%) as yellowcrystals.

¹H NMR (CDCl₃, 400 MHz) δ: 3.63 (2H, s), 7.07 (1H, d, J=9 Hz), 7.33 (2H,d, J=9 Hz), 7.62 (2H, d., J=8 Hz), 7.71 (1H, t, J=8 Hz), 7.8-8.0 (5H,m), 8.09 (1H, d, J=8 Hz), 8.1-8.3 (2H, m), 8.50 (1H, s), 9.75 (1H, s),9.91 (1H,

Example 525-[4-[(5-Methylthiophen-2-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (16mg, 0.050 mmol) obtained in Example 1, (3),5-methylthiophene-2-carboxylic acid (14 mg, 0.101 mmol), andO-(benzotriazol-1-yl)-N, N, N′, N′-tetramethyluroniumhexafluorophosphate (21 mg, 0.055 mmol) were dissolved in DMF (2.0 mL),then the solution was added with triethylamine (10 mg, 0.101 mmol), andthe mixture was stirred over night. The reaction mixture was treated ina conventional manner to give the title compound (10 mg, yield 45%) aswhite crystals.

¹H NMR (CDCl₃, 400 MHz) δ: 2.54 (3H, s), 3.60 (2H, s), 6.79 (1H, d, J=2Hz), 7.04 (1H, d, J=9 Hz), 7.25 (1H, d, J=9 Hz), 7.45 (1H, d, J=2 Hz),7.5-7.8 (7H, m), 7.86 (1H, d, J=8 Hz), 8.05 (1H, d, J=8 Hz), 8.26 (1H,s).

Example 535-[3-[(2-Chlorophenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(1) 5-(3-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using 1-nitro-2-naphthyl trifluoromethanesulfonate (6.94 g, 18.5mmol), and tert-butyl (3-aminophenyl)carbamate, the title compound (1.02g, yield 17%) was obtained as brown crystals in the same manner as thatof Example 1, (1), (2) and (3).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.11 (1H, d, J=12 Hz), 3.66 (1H, d, J=12Hz), 5.23 (2H, s), 6.35 (1H, s), 6.39 (1H, d, J=8 Hz), 6.52 (1H, d, J=13Hz), 7.0-7.1 (2H, m), 7.58 (1H, t, J=8 Hz), 7.65 (1H, t, J=8 Hz), 7.70(1H, d, J=8 Hz), 7.91 (1H, d, J=8 Hz), 8.23 (1H, d, J=8 Hz), 10.86 (1H,s).

(2)5-[3-[(2-Chlorophenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

2-Chlorophenylacetic acid (31 mg, 0.18 mmol) was treated with thionylchloride in the same manner as that of Example 13, and then by using theresultant together with5-(3-aminophenyl)-1H-naphtho[1,21)][1,4]diazepine-2,4(3H,5H)-dione (28mg, 0.088 mmol), the title compound (10 mg, yield 24%) was obtained asyellow crystals in the same manner as that of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.14 (1H, d, J=12 Hz), 3.72 (1H, d, J=12Hz), 3.79 (2H, s), 7.0-7.1 (2H, m), 7.2-7.3 (2H, m), 7.3-7.5 (3H, m),7.47 (1H, a), 7.5-7.7 (4H, m), 7.92 d, J=8 Hz), 8.24 (1H, d, J=8 Hz),10.33 (1H, s), 10.90 (1H, s).

5-[4-[(2,4,6-Trimethylbenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

2,4,6-Trimethylbenzoic acid (25 mg, 0.15 mmol) was treated with thionylchloride in the same manner as that of Example 13, and then by using theresultant together with5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32mg, 0.1 mmol) obtained in Example 1, (3), the title compound (6 mg,yield 13%) was obtained as slightly brown crystals in the same manner asthat of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 2.25 (6H, s), 2.27 (3H, s), 3.16 (1H, d,J=12 Hz), 3.70 (1H, d, J=12 Hz), 6.93 (2H, s), 7.04 (1H, d, J=9 Hz),7.20 (2H, d, J=8 Hz), 7.5-7.7 (3H, m), 7.79 (2H, d, J=9 Hz), 7.92 (1H,d, J=7 Hz), 8.26 (1H, d, J=8 Hz), 10.45 (1H, s), 10.87 (1H, s).

Example 555-[4-(Cyclohexylcarbonylamino)-phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(1) 1-Nitro-5,6,7,8-tetrahydro-2-naphthyl trifluoromethanesulfonate

1-Nitro-5,6,7,8-tetrahydro-2-naphthol (6.95 g, 36 mmol) was dissolved indichloromethane (70 mL), and the solution was added with triethylamine(5.52 mL, 39.6 mmol). This mixture was added dropwise withtrifluoromethanemethanesulfonic anhydride (6.2 mL, 38 mina over 15minutes with stirring under ice cooling, and then the mixture wasstirred for 1 hours and 30 minutes under ice cooling. This reactionmixture was added with cold water, and the mixture was stirred for 10minutes. The dichloromethane layer was washed with saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated, and theresidue was purified by silica gel column chromatography (hexane/ethylacetate=5/1) to give the title compound (10.15 g, yield 87%) as yellowoil,

¹H NMR (CDCl₃, 400 MHz) δ: 1.8-1.9 (4H, m), 2.7-2.9 (4H, m), 7.21 (1H,d, J=9 Hz.,), 7.29 (1H, d, J=9 Hz).

(2) tert-Butyl[4-[(1-nitro-5,6,7,8-tetrahydro-2-naphthyl)amino]phenyl]carbamate

By using 1-nitro-5,6,7,8-tetrahydro-2-naphthyl trifluoromethanesulfonate(2.23 g, 6.86 mmol), and tert-butyl (4-aminophenyl)carbamate (1.43 g,6.86 mmol), the title compound (2.30 g, yield 87%) was obtained as redcrystals in the same manner as that of Example 1, (1).

¹H NMR (CDCl₃, 400 MHz) δ: 1.52 (9H, s), 1.7-1.9 (4H, m), 2.6-2.9 (4H,In), 6.41 (1H, s), 6.97 (1H, d, J=9 Hz), 7.01 (1H, d, J=9 Hz), 7.04 (2H,d, J=9 Hz), 7.31 (2H, d, J=9 Hz).

(3) tert-Butyl[4-[(1-amino-5,6,7,8-tetrahydro-2-naphthyl)amino]phenyl]carbamate

tert-Butyl[4-[(1-nitro-5,6,7,8-tetrahydro-2-naphthyl)amino]phenyl]carbamate (7.66g, 20 mmol) was dissolved in tetrahydrofuran (77 mL) and methanol (77mi,), the solution was added with 10% palladium-carbon (0.77 g), and themixture was stirred at room temperature for 42 hours under a hydrogenatmosphere. The catalyst was separated by filtration, then the solventwas evaporated under reduced pressure, and the residue was washed withhexane to obtain the title compound (6.71 g, yield 95%) as pale browncrystals.

NMR (CDCl₃, 400 MHz) δ: 1.50 (9H, s), 1.7-1.9 (4H, m), 2.4-2.6 (2H, m),2.7-2.8 (2H, m), 6.24 (1H, s), 6.52 (1H, d, J=8 Hz), 6.63 (2H, d, J=8Hz), 6.87 (1H, d, J=9 Hz), 7.14 (2H, d, J=8 Hz).

(4) Ethyl3-[[2-[[(4-[(tert-butoxycarbonyl)amino]phenyl]amino]-5,6,7,8-tetrahydro-1-naphthyl]amino]-3-oxopropionate

By using tert-butyl[4-[(1-amino-5,6,7,8-tetrahydro-2-naphthyl)amino]phenyl]carbamate (6.01g, 174 mmol), a crude product (9.7 g) was obtained in the same manner asthat of Example 1, (3). The crude product was purified by silica gelcolumn chromatography (hexane/ethyl acetate=1/1) to give the titlecompound (3.48 g, yield 44%) as pale brown crystals.

¹H NMR (CDCl₃, 400 MHz) δ: 1.31 (3H, t, J=7 Hz), 1.50 (9H, E), 1.7-1.9(4H, m), 2.6-2.8 (4H, m), 3.51 (2H, s), 4.25 (2H, q, J=7 Hz), 6.08 (1H,s), 6.31 (1H, s), 6.89 (2H, d, J=9 Hz), 6.92 (1H, d, J=9 Hz), 7.07 (1H,d, J=9 Hz), 7.19 (2H, d, J=9 Hz), 8.66 (1H, s).

(5)5-[4-(tert-Butoxycarbonyl)aminoophenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using ethyl3-[[2-[[4-[(tert-butoxycarbonyl)amino]phenyl]amino]-5,6,7,8-tetrahydro-1-naphthyl]amino]-3-oxopropionate(3.48 g, 7.44 mmol), a crude product (4.6 g) was obtained in the samemanner as that of Example 1, (3). The crude product was purified bysilica gel column chromatography (hexane/ethyl acetate=1/2) to give thetitle compound (2.07 g, yield 66%) as pale brown amorphous.

(6)5-(4-Aminophenyl)-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-[4-(tert-butoxycarbonyl)aminophenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(2.07 g, 4.91 mmol), the title compound (1.21 g, yield 77%) was obtainedas pale brown crystals in the same manner as that of Example 1, (3).

¹H NMR (DMSO-de 400 MHz) δ: 1.6-1.9 (4H, m), 2.29 (3H, s), 2.5-2.8 (3H,m), 2.9-3.0 (1H, m), 2.98 (1H, d, J=12 Hz), 3.47 (1H, d, J=12 Hz), 5.20(2H, s), 6.54 (2H, d, J=9 Hz), 6.66 (1H, d, J=9 Hz), 6.76 (2H, d, J=9Hz), 6.85 (1H, d, J=9 Hz), 9.79 (1H, s).

(7)5-[4-(Cyclohexylcarbonylamino)phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho(1,2-[b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-8,9,10,11-tetrahydro-1H-naphtho[2,1-b][1,4]diazepine-2,4(3H,5H)-dione,and cyclohexanecarbonyl chloride, the title compound was obtained in thesame manner as that of Example 1, (4).

¹H NMR (CDCl₃, 400 MHz) δ: 1.2-1.4 (4H, m), 1.4-2.0 (10H, m), 2.2-2.3(1H, m), 2.6-2.8 (4H, m), 3.46 (1H, d, J=12 Hz), 3.51 (1H, d, J=12 Hz),6.67 (1H, d, J=9 Hz), 6.81 (1H, d, J=8 Hz), 7.08 (2H, d, J=9 Hz), 7.49(2H, d, J=9 Hz), 7.59 (1H, s), 8.25 (1H, s).

Example 561-[4-(2,3-Dimethylbenzoyl)aminophenyl]-6-methyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione(1) tert-Butyl-4-(2-amino-3-methylphenylamino)phenylcarbamate

By using 2-methyl-6-hydroxynitrobenzene, the title compound was obtainedin the same manner as that of Example 1.

¹H NMR (CDCl₃, 400 MHz) δ: 1.50 (9H, s), 2.22 (3H, s), 3.75 (2H, br s),5.04 (1H, br s), 6.27 (1H, br s), 6.6-6.7 (3H, m), 6.8-7.0 (2H, m), 7.17(2H, d, J=8 Hz).

(2)1-(4-tert-Butoxycarbonylaminophenyl)-6-methyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione

tert-Butyl 4-(2-amino-3-methylphenylamino)phenylcarbamate (294 mg, 0.938m mmol) was dissolved in THE′ (30 mL), and then the solution was addeddropwise with malonyl chloride (91 μL, 0.938 mmol) under ice cooling.After the disappearance of the starting materials was confirmed, thereaction mixture was added with aqueous sodium hydrogencarbonate, andethyl acetate, and the organic layer was separated. The organic layerwas washed with brine and water, and then dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography (chloroform tochloroform/methanol=100/1) to obtain the title compound (119 mg, yield33%).

¹H NMR (CDCl₃, 400 MHz) δ; 1.51 (9H, s), 2.41 (3H, s), 3.50 (2H, s),6.53 (1H, br s), 6.80 (1H, d, J=7 Hz), 6.99 (1H, t, J=8 Hz), 7.0-7.2(3H, m), 7.38 (2H, d, J=9 Hz), 7.63 (1H, br s).

(a) 1-(4-Aminophenyl)-6-methyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione

In the same manner as that of Example 1, (3), the title compound wasobtained.

¹H NMR (CDCl₃, 400 MHz) δ: 2.40 (3H, s), 3.48 (2H, s), 3.74 (2H, br s),6.67 (2H, d, J=9 Hz), 6.86 (1H, d, J=8 Hz), 6.9-7.1 (4H, m), 7.74 (1H,br s).

(4)1-[4-(2,3-Dimethylbenzoyl)aminophenyl]-6-methyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione

2,3-Dimethylbenzoic acid (21 mg, 0.140 mmol) was made into acid chloridein a conventional manner. By using1-(4-aminophenyl)-6-methyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione (20mg, 0.071 mmol) mentioned above, and 2,3-dimethylbenzoyl chloridementioned above, the title compound (27 mg, yield 92%) was obtained inthe same manner as that of Example 1.

¹H NMR (DMSO-d₆, 400 MHz) δ: 2.26 (3H, s), 2.29 (3H, s), 2.38 (3H, s),3.06 (1H, d, J=12 Hz), 3.57 (1H, d, J=12 Hz), 6.75 (1H, d, J=8 Hz),7.0-7.3 (7H, m), 7.78 (2H, d, J=8 Hz), 10.01 (1H, s), 10.40 (1H, s).

Example 575-[4-[(2-Ethylbenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

2-Ethylbenzoic acid (23 mg, 0.15 mmol) was treated with thionyl chloridein the same manner as that of Example 13, and then by using theresultant together with5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32rag, 0.1 mmol) obtained in Example 1, (3), the title compound (26 mg,yield 58%) was obtained as slightly brown crystals in the same manner asthat of Example 1, (4).

¹H NMR (DMSO-de, 400 MHz) δ: 1.18 (3H, t, J=7 Hz), 2.75 (2H, q, J=7 Hz),3.16 (1H, d, J=11 Hz), 3.71 (1H, d, J=11 Hz), 7.03 (1H, d, J=9 Hz), 7.21(2H, d, J=8 Hz), 7.3-7.5 (4H, m), 7.6-7.7 (3H, m), 7.81 (2H, d, J=8 Hz),7.93 (1H, d, J=7 Hz), 8.26 (1H, d, J=8 Hz), 10.49 (1H, s), 10.89 (1H,s).

5-[4-[(6-Methylpyridin-2-yl)carbonylamino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2.4(3H,5H)-dione

6-Methylpyridine-2-carboxylic acid (17 mg, 0.124 mmol) was made intoacid chloride in a conventional manner. By using5-(4-aminophenyl)-1,5,8,9,10,11-hexahydronaphtho[1,2-b][1,4]diazepine-2,4-dione(20 mg, 0.062 mmol) obtained in Example 55, and6-methylpyridine-2-carboxylic acid chloride mentioned above, the titlecompound (9 mg, yield 33%) was obtained in the same manner as that ofExample 1.

¹H NMR (CDCl₃, 400 MHz) δ: 1.7-2.1 (4H, m), 2.63 (3H, s), 2.6-2.8 (4H,m), 3.4-3.6 (2H, m), 6.73 (1H, d, J=8 Hz), 6.85 (1H, d, J=9 Hz), 7.22(2H, d, J=9 Hz), 7.33 (1H, d, J=7 Hz), 7.7-7.9 (4H, m), 8.08 (1H, d, J=8Hz), 10.11 (1H, s).

Example 595-[4-[(2-Methylpyridin-3-yl)carbonylamino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

2-Methylpyridine-3-carboxylic acid (17 mg, 0.124 mmol) was made intoacid chloride in a conventional manner. By using5-(4-aminophenyl)-1,5,8,9,10,11-hexahydronaphtho[1,2-b][1,4]diazepine-2,4-dione(20 mg, 0.062 mmol) obtained in Example 55, and2-methylpyridine-3-carboxylic acid chloride mentioned above, the titlecompound (20 mg, yield 73%) was obtained in the same manner as that ofExample 1.

¹H NMR (DMSO-c16, 400 MHz) δ: 1.6-1.9 (4H, m), 2.57 (3H, s), 2.5-2.8(3H, m), 2.8-3.0 (1H, m), 3.03 (1H, d, J=12 Hz), 3.55 (1H, d, J=12 Hz),6.65 (1H, d, J=8 Hz), 6.88 (1H, d, J=9 Hz), 7.14 (2H, d, J=9 Hz),7.3-7.4 (1H, m), 7.76 (2H, d, J=8 Hz), 7.86 (1H, d, J=8 Hz), 8.55 (1H,d, J=5 Hz), 9.87 (1H, s), 10.54 (1H, s).

Example 601-[4-(2,4-Dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-3-(2-methylphenyl)thiourea

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (150mg, 0.473 mmol), and o-tolyl isothiocyanate (159 μL, 1.183 mmol), thetitle compound (66 mg, yield 30%) was obtained in the same manner asthat of Example 24.

¹H NMR (DMSO-d₆, 400 MHz) δ: 2.25 (3H, s), 3.15 (1H, d, J=12 Hz), 3.69(1H, d, J=12 Hz), 7.00 (1H, d, J=9 Hz), 7.1-7.3 (6H, m), 7.5-7.8 (5H,m), 7.92 (1H, d, J=8 Hz), 8.25 (1H, d, J=8 Hz), 9.42 (1H, s), 9.76 (1H,s), 10.89 (1H, s).

Example 615-[4-(2-Methoxy-3-methylbenzoyl)aminophenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

2-Methoxy-3-methylbenzoic acid (25 mg, 0.15 mmol) was treated withthionyl chloride in the same manner as that of Example 13, and then byusing the resultant together with5-(4-aminophenyl)-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(39 mg, 0.12 mmol) obtained in Example 55, the title compound (52 mg,yield 92%) was obtained as slightly brown crystals in the same manner asthat of Example 1, (4),

¹H NMR (DMSO-d₆, 400 MHz) δ: 1.6-1.9 (4H, m), 2.29 (3H, s), 2.5-2.8 (3H,m), 2.9-3.0 (1H, m), 3.04 (1H, d, J=12 Hz), 3.56 (1H, d, J=12 Hz), 3.75(3H, s), 6.66 (1H, d, J=9 Hz), 6.88 (1H, d, J=8 Hz), 7.1-7.2 (3H, m),7.3-7.4 (2H, m), 7.77 (2H, d, J=9 Hz), 9.86 (1H, 10.36 (1H, s).

Example 625-[4-(2,3-Dichlorobenzoyl)aminophenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1,5,8,9,10,11-hexahydronaphtho-1H-naphtho[1,2-b][1,4]diazepine-2,4-dione(40 mg, 0.124 mmol) obtained in Example 55, (6), and 2,3-dichlorobenzoylchloride (40 mg, 0.187 mmol), the title compound (50 mg, yield 81%) wasobtained as white crystals in the same manner as that of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 1.6-1.9 (4H, m), 2.5-2.9 (4H, m), 3.01 (1H,d, J=12 Hz), 3.55 (1H, d, J=42 Hz), 6.64 (1H, d, J=8 Hz), 6.87 (1H, d,J=8 Hz), 7.14 (2H, d, J=8 Hz), 7.48 (1H, t, J=8 Hz), 7.56 (1H, d, J=8Hz), 7.72 (2H, d. J=9 Hz), 7.76 (1H, d, J=8 Hz), 9.86 s), 10.69 (1H, s).

Example 635-[4-(2,3-Dimethylbenzoylamino)-3-hydroxyphenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(1) tert-Butyl 4-(1-aminonaphthalen-2-ylamino)-2 methoxyphenylcarbamate

By using Cert-butyl2-methoxy-4-(1-nitronaphthalen-2-ylamino)phenylcarbamate, the titlecompound was obtained in the same manner as that of Example 1, (2).

¹H NMR (CDCl₃, 400 MHz) δ: 1.51 (9H, s), 3.72 (3H, s), 4.35 (2H, br s),5.14 (1H, br s), 6.27 (1H, d, J=2 Hz), 6.34 (1H, dd, J=2 Hz, 8 Hz), 6.77(1H, br s), 7.27 (1H, d, J=8 Hz), 7.30 (1H, d, J=9 Hz), 7.4-7.5 (2H, m),7.7-7.9 (2H, m).

(2) tert-Butyl4-[2,4-dioxo-3,4-dihydro-1H-naphtho[2,1-b][1,4]diazepin-5(2H)-yl]-2-methoxyphenylcarbamate

By using tert-butyl4-(1-aminonaphthalen-2-ylamino)-2-methoxyphenylcarbamate, the titlecompound was obtained in the same manner as that of Example 42, (1).

¹H NMR (CDCl₃, 400 MHz) δ: 1.52 (9H, s), 3.5-3.7 (2H, m), 3.83 (3H, s),6.7-6.8 (2H, 7.07 (1H, d, J=9 Hz), 7.10 (1H, br s), 7.5-7.7 (2H, m),7.69 (1H, t, J=8 Hz), 7.85 (1H, d, J=7 Hz), 8.05 (1H, d, J=9 Hz), 8.11(1H, d, J=9 Hz), 8.25 (1H, br s).

(3)5-(4-Amino-3-methoxyphenyl)-1H-naphtho[2,1-b][1,4]diazepine-2,4(3H,5H)-dione

By using tert-butyl4-[2,4-dioxo-3,4-dihydro-1H-naphtho[2,1-b][1,4]diazepin-5(2H)-yl]-2-methoxyphenylcarbamate,the title compound was obtained in the same manner as that of Example 1,(3).

¹H NMR (CDCl₃, 400 MHz) δ: 3.56 (1H, d, J=12 Hz), 3.60 (1H, d, J=12 Hz),3.79 (3H, s), 3.90 (2H, br s), 6.6-6.8 (3H, m), 7.12 (1H, d, J=9 Hz),7.5-7.6 (2H, m), 7.6-7.7 (1H, m), 7.84 (1H, d, J=8 Hz), 8.09 (1H, d, J=9Hz), 8.68 (1H, br s).

(4)5-[4-(2,3-Dimethylbenzoylamino)-3-methoxyphenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-amino-3-methoxyphenyl)-1H-naphtho[2,1-b][1,4]diazepine-2,4(3H,5H)-dione,and 2,3-dimethylbenzoyl chloride, the title compound was obtained in thesame manner as that of Example 1, (4).

¹H NMR (CDCl₃, 400 MHz) δ: 2.33 (3H, s), 2.39 (3H, s), 3.61 (2H, s),3.82 (3H, s), 6.8-6.9 (2H, m), 7.11 (1H, d, J=9 Hz), 7.18 (1H, t, J=8Hz), 7.2-7.3 (1H, m), 7.32 (1H, d, J=7 Hz), 7.5-7.7 (2H, m), 7.70 (1H,t, J=7 Hz)), 7.86 (1H, d, J=8 Hz), 8.0-8.1 (2H, m), 8.50 (1H, br s),8.61 (1H, d, J=9 Hz).

(5)5-[4-(2,3-Dimethylbenzoylamino)-3-hydroxyphenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-[4-(2,3-dimethylbenzoylamino)-3-methoxyphenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione,the title compound was obtained in the same manner as that of Example18.

¹H NMR (DMSO-d₆, 400 MHz) δ: 2.28 (6H, s), 3.14 (1H, d, J=12 Hz), 3.69(1H, d, J=12 Hz), 6.66 (1H, d, J=8 Hz), 6.77 (1H, s), 7.07 (1H, d, J=9Hz), 7.17 (1H, t, J=7 Hz), 7.27 (1H, d, J=7 Hz), 7.28 (1H, d, J=7 Hz),7.59 (1H, t, J=7 Hz), 7.66 (1H, t, J=7 Hz), 7.71 (1H, d, J=9 Hz), 7.80(1H, d, J=9 Hz), 7.91 (1H, d, J=8 Hz), 8.23 (1H, d, J=8 Hz), 9.34 (1H,br s), 10.88 (1H, s).

Example 645-[4-(2-Chloro-3-methoxybenzoylamino)phenyl]-1,3-dihydronaphtho[1,2-e]-1,4-diazepin-2-one(1) 5-(4-Aminophenyl)-1H-naphtho[1,2-e][1,4]diazepin-2(3H)-one

5-(4-Bromophenyl)-1H-naphtho[1,2-e][1,4]diazepin-2 (3H)-one (380 mg,1.04 mmol), benzophenone imine (349 mg, 2.08 mmol), sodium tert-butoxide(200 mg, 2.08 mmol), palladium(II) acetate (23 mg, 0.104 mmol), and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (60 mg, 0,208 mmol) weredissolved in anhydrous dioxane (5 mL), and the solution was stirred at110° C. for 16 hours. The reaction mixture was left to cool, and thenpoured into water, and the mixture was extracted with chloroform. Theorganic layer was washed with saturated brine, and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure, andthe residue was purified by silica gel column chromatography(chloroform/methanol=100/1) to give the title compound (154 mg, yield49%).

¹H NMR (DMSO-d₆, 40011 Hz) δ: 3.67 (1H, d, J-10 Hz), 4.42 (1H, d, J=10Hz), 5.57 (2H, s), 6.54 (2H, d, J=8 Hz), 7.24 (2H, d, J=8 Hz), 7.33 (1H,d, J=9:14z), 7.6-7.8 (3H, m), 7.9-8.1 (1H, m), 8.3-8.4 (1H, m), 10.67(1H, br

(2)5-[4-(2-Chloro-3-methoxybenzoylamino)phenyl]-1,3-dihydronaphtho[1,2-e]-1,4-diazepin-2-one

By using 5-(4-aminophenyl)-1H-naphtho[1,2-e][1,4]diazepin-2 (3H)-one (90mg, 0.3 mmol) obtained above, and 2-chloro-3-methoxybenzoyl chloride(0.45 mmol), the title compound (78 mg, yield 55%) was obtained in thesame manner as that of Example 1, (4).

¹H NMR (DMSO-d₆, 500 MHz) δ: 3.79 (1H, (1, J=10 Hz), 3.91 (3H, s), 4.56(1H, d, J=10 Hz), 7.15 (1H, d, J=7 Hz), 7.2-7.3 (2H, m), 7.43 (1H, t,J=8 Hz), 7.55 (2H, d, J=8 Hz), 7.7-7.8 (5H, m), 8.03 (1H, d, J=9 Hz),8.37 (1H, d, J=9 Hz), 10.71 (1H, s), 10.85 (1H, s).

Example 655-[4-[(4-Dimethylaminobenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

4-Dimethylaminobenzoic acid (33 mg, 0.2 mmol) was treated with oxalylchloride in the same manner as that of Example 40, and then by using theresultant together with5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32mg, 0.1 mmol) obtained in Example 1, (3), the title compound (12 mg,yield 26%) was obtained as pale brown crystals in the same manner asthat of Example 1, (4). The structure was confirmed by NMR and MS.

MS (FAB) m/z: 465, 929

Example 665-[4-[2-(2,4-Dichlorophenoxy)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

2,4-Dichlorophenoxyacetic acid (42 mg, 0.190 mmol) was made into acidchloride in a conventional manner. By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30mg, 0.095 mmol) obtained in Example 1, (3), and2,4-dichlorophenoxyacetic acid chloride mentioned above, the titlecompound (11 mg, yield 22%) was obtained in the same manner as that ofExample 1.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.71 (1H, CI, J=12Hz), 4.88 (′2H, s), 6.99 (1H, d. J=9 Hz), 7.11 (1H, d, J=9 Hz), 7.20(2H, d, J=9 Hz), 7.38 (1H, dd, J=2 Hz, 9 Hz), 7.5-7.7 (6H, m), 7.92 (1H,d, J=9 Hz), 8.25 (1H, d, J=9 Hz), 10.36 (1H, s), 10.92 (1H, s).

Example 675-[4-[2-(2-Methylphenoxy)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

(2-Methylphenoxy)acetic acid (32 mg, 0.193 mmol) was made into acidchloride in a conventional manner. By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30mg, 0.095 mmol) obtained in Example 1, and (2-methylphenoxy)acetic acidchloride mentioned above, the title compound (21 mg, yield 48%) wasobtained in the same manner as that of Example 1.

¹H NMR (DMSO-d₆, 400 MHz) δ: 2.25 (3H, s), 3.15 (1H, d, J=12 Hz), 3.71(1H, d, J=12 Hz), 4.74 (2H, s), 6.8-6.9 (2H, m), 6.99 (1H, d, J=9 Hz),7.1-7.3 (4H, m), 7.60 (1H, t, J=9 Hz), 7.6-7.8 (5H, m), 7.92 (1H, d, J=9Hz), 8.25 (1H, d, J=9 Hz), 10.23 (1H, s), 10.92 (1H, s).

Example 68N-[4-(2,4-Dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)butyl]-2-chloro-3-methoxybenzamide

By using N-(tert-butoxycarbonyl)-1,4-diaminobutane as the startingmaterial,5-(4-aminobutyl)-1H-naphtho[2,1-b][1,4]diazepine-2,4(3H,5H)-dione wasobtained in the same manner as that of Example 42, (1) and (2). By using5-(4-aminobutyl)-1H-naphtho[2,1-b][1,4]diazepine-2,4(3H,5H)-dione (30mg, 0.1 mmol), and 2-chloro-3-methoxybenzoyl chloride (0.15 mmol), thetitle compound (26 mg, yield 56%) was obtained in the same manner asthat of Example 1, (4).

¹H NMR (DMSO-d₆, 500 MHz) δ: 1.4-1.5 (3H, m), 1.5-1.6 (1H, m), 3.08 (1H,d, J=12 Hz), 3.1-3.2 (2H, m), 3.53 (1H, d, J=12 Hz), 3.8-3.9 (1H, m),3.91 (3H, s), 4.3-4.4 (1H, m), 6.86 (1H, d, J=8 Hz), 7.21 (1H, d, J=8Hz), 7.2-7.3 (1H, m), 7.6-7.7 (2H, m), 7.78 (1H, d, J=9 Hz), 7.94 (1H,d, J=9 Hz), 8.05 (1H, d, J=8 Hz), 8.25 (1H, d, J=9 Hz), 8.34 (1H, t, J=6Hz), 10.78 (1H, br s).

Example 695-[4-(2-Chloro-3-hydroxybenzoylamino)phenyl]-1,3-dihydronaphtho[1,2-e]-1,4-diazepin-2-one

By using5-[4-(2-chloro-3-methoxybenzoylamino)phenyl]-1,3-dihydronaphtho[1,2-e]-1,4-diazepin-2-one(65 mg, 0.138 mmol) obtained in Example 64, the title compound (18 mg,yield 29%) was obtained in the same manner as that of Example 18.

¹H NMR (DMSO-d₆, 500 MHz) δ: 3.92 (1H, d, J=10 Hz), 4.69 (1H, d, J=10Hz), 7.09 (1H, d, J=7 Hz), 7.19 (1H, d, J=8 Hz), 7.36 (1H, t, J=8 Hz),7.44 (1H, d, J=9 Hz), 7.67 (2H, d, J=9 Hz), 7.8-7.9 (5H, m), 8.16 (1H,d, J=9 Hz), 8.50 (1H, d, J=9 Hz), 10.77 (1H, s), 10.96 (1H, br s).

5-[4-(2-Acetylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 1, (3), and 2-acetylbenzoyl chloride, the titlecompound (yield 27%) was obtained in the same manner as that of Example1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 1.65 (3H, s), 3.25 (1H, d, J=12 Hz), 3.82(1H, d, J=12 Hz), 6.94 (1H, s), 7.1-7.2 (1H, m), 7.40 (2H, d, J=9 Hz),7.6-7.9 (9H, m), 8.01 (1H, d, J=8 Hz), 8.35 (1H, d, J=9 Hz), 11.02 (1H,br s).

Example 715-[4-(2-tert-Butylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30mg, 0.095 mmol) obtained in Example 1, (3), and 2-tert-butylbenzoylchloride (0.143 mmol), the title compound (20 mg, yield 44%) wasobtained in the same manner as that of Example 1, (4).

¹H NMR (DMSO-d₆, 500 MHz) δ: 1.52 (9H, s), 3.28 (1H, d, J=12 Hz), 3.83(1H, d, J=12 Hz), 7.16 (1H, d, J=9 Hz), 7.33 (2H, d, J=8 Hz), 7.42 (2H,s), 7.54 (1H, br s), 7.66 (1H, d, J=8 Hz), 7.72 (1H, t, J=8 Hz), 7.7-7.8(2H, m), 7.91 (2H, d, J=8 Hz), 8.05 (1H, d, J=8 Hz), 8.38 (1H, d, J=9Hz), 10.69 (1H, s), 11.03 (1H, s).

Example 725-[2-(2-Iodobenzoyl)aminoethyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(1) tert-Butyl [2-[(1-nitro-2-naphthyl)amino]ethyl]carbamate

1-Nitro-2-naphthyl trifluoromethanesulfonate (1.61 g, 5 mmol),N-(tert-butoxycarbonyl)ethylenediamine (0.80 g, 5 mmol), potassiumcarbonate (0.69 g, 5 mmol), and toluene (20 mL) were mixed, and themixture was refluxed by heating for 16 hours. This reaction mixture wasadded with water, the mixture was extracted with ethyl acetate, and theorganic layer was washed with saturated brine, and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure togive yellow crystals, and the crystals were washed twice with hexane (20ml.,) to obtain the title compound (1.50 g, yield 91%) as yellowcrystals.

¹H NMR (CDCl₃, 400 MHz) δ: 1.46 (9H, s), 3.4-3.5 (2H, m), 3.5-3.7 (2H,m), 4.82 (1H, br s), 7.17 (1H, d, J=9 Hz), 7.34 (1H, t, J=7 Hz), 7.60(1H, ddd, J=1 Hz, 7 Hz, 8 Hz), 7.68 (1H, d, J=8 Hz), 7.82 (1H, d, J=9Hz), 8.69 (1H, d, J=9 Hz), 8.76 (1H, br s).

(2) text-Butyl [2-[(1-amino-2-naphthyl)amino]ethyl]carbamate

tert-Butyl [2-[(1-nitro-2-naphthyl)amino]ethyl]carbamate (746 mg, 2.25mmol) was dissolved in tetrahydrofuran (7.5 mL), and methanol (7.5 mL),the solution was added with platinum oxide (7.5 mg), and the mixture wasstirred at room temperature for 7 hours under a hydrogen atmosphere. Thecatalyst was separated by filtration, then the solvent was evaporatedunder reduced pressure, and the residue was washed with hexane to givethe title compound (646 mg, yield 95%) as brown crystals.

¹H NMR (CDCl₃, 400 MHz) δ: 1.46 (9H, s), 3.1-3.6 (5H, m), 3.80 (2H, br5), 4.88 (1H, br s), 7.11 (1H, d, J=9 Hz), 7.2-7.3 (1H, m), 7.41 (2H, t,J=8 Hz), 7.73 (2H, d,

(3)5-[2-(tert-Butoxycarbonyl)aminoethyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

tert-Butyl [2-[(1-amino-2-naphthyl)amino]ethyl]carbamate (646 mg, 2.14mmol) was dissolved in dry tetrahydrofuran (65 mL), the solution wasadded with malonyl chloride (0.23 mL, 2.3 mmol) with stirring under icecooling, and then the mixture was stirred under ice cooling for 1 hourand then at room temperature for 2 hours. This reaction mixture wasadded with saturated aqueous sodium hydrogencarbonate and water, themixture was extracted with ethyl acetate, and the organic layer waswashed with saturated brine, and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure to give brown oil (1.1g), and the oil was purified by silica gel column chromatography(methanol/chloroform= 1/20) to obtain brown oil (0.5 g). The oil wasfurther purified by silica gel column chromatography (hexane/ethylacetate=1/1) to give the title compound (16 mg, yield 2%) as whitepowder.

¹H NMR (CDCl₃, 400 MHz) δ: 1.21 (9H, s), 3.3-3.5 (4H, m), 3.9-4.1 (1H,m), 4.3-4.4 (1H, m), 4.96 (1H, br s), 7.51 (1H, d, J=9 Hz), 7.59 (1H, t,J=7 Hz), 7.67 (1H, t, J=7 Hz), 7.79 (1H, d, J=9 Hz), 7.88 (1H, d, J=8Hz), 8.07 (1H, d, J=7 Hz), 8.79 (1H, br s).

(4)5-[2-(2-Iodobenzoyl)aminoethyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

5-[2-(tert-Butoxycarbonyl)aminoethyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(16 mg, 0.043 mmol) was dissolved in dichloromethane (4 mL), thesolution was added with trifluoroacetic acid (0.1 mL), and the mixturewas stirred at room temperature for 19 hours. This reaction mixture wasadded with saturated aqueous sodium hydrogencarbonate (8 mL) withstirring under ice cooling, and the mixture was stirred for 5 minutes.Further, the mixture was added with 2-iodobenzoyl chloride (0.22 mmol)dissolved in dichloromethane (4 mL) with stirring under ice cooling.This reaction mixture was stirred under ice cooling for 30 minutes, andthen at room temperature for 30 minutes. The dichloromethane layer waswashed with saturated brine, and dried over anhydrous sodium sulfate.The solvent was evaporated, and the residue was purified by silica gelcolumn chromatography (methanol/chloroform=1/50), and thenrecrystallized from ethyl acetate/hexane to give the title compound (9mg, yield 42%) as white crystals. The structure was confirmed by NMR andMS.

MS (FAB) m/z: 500, 999

Example 735-[3-[(2-Iodobenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

2-Iodobenzoic acid (50 mg, 0.2 mmol) was treated with thionyl chloridein the same manner as that of Example 13, and then by using theresultant together with5-(3-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32mg, 0.1 mmol) obtained in Example 53, (1), the title compound (21 mg,yield 38%) was obtained as pale brown crystals in the same manner asthat of Example 1, (4). The structure was confirmed by NMR and MS.

MS (FAB) m/z: 548, 1095

Example 746,7-Dimethyl-1-[4-(2-iodobenzoyl)aminophenyl]-1H-1,5-benzodiazepine-2,4(3H,5H)-dione

2-Iodobenzoic acid (34 mg, 0.137 mmol) was made into acid chloride in aconventional manner. By using1-(4-aminophenyl)-6,7-dimethyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione(20 mg, 0.068 rum& obtained in Example 56, and 2-iodobenzoyl chloridementioned above, the title compound (31 mg, yield 87%) was obtained inthe same manner as that of Example 1.

¹H NMR (DMSO-d₆, 400 MHz) δ: 2.24 (3H, s), 2.25 (3H, s), 3.03 (1H, d,J=12 Hz), 3.56 (1H, d, J=12 Hz), 6.66 (1H, d, J=9 Hz), 6.98 (1H, d, 7.13(2H, d, J=9 Hz), 7.2-7.3 (1H, m), 7.4-7.6 (2H, m), 7.7-7.8 (2H, m), 7.94(1H, d, J=9 Hz), 10.07 (1H, s), 10.56 (1H, s).

Example 755-[4-[(1-Methylpiperidin-4-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dionehydrochloride (1)5-[4-[(1-Methylpiperidin-4-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 1, (3), and 1-methylpiperidine-4-carbonyl chloride,the title compound (yield 100%) was obtained in the same manner as thatof Example 1, (4).

(2)5-[4-[(1-Methylpiperidin-4-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dionehydrochloride

By using5-[4-[(1-methylpiperidin-4-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione,the title compound was obtained in the same manner as that of Example40, (2).

¹H NMR (DMSO-d₆, 400 MHz) δ: 1.8-2.1 (4H, m), 2.5-2.7 (1H, m), 2.75 (3H,s), 2.95 (2H, t, J=11 Hz), 3.14 (1H, dd, 12 Hz), 3.4-3.5 (2H, m), 3.70(1H, d, J=12 Hz), 6.97 (1H, d, J=9 Hz), 7.17 (2H, d, J=9 Hz), 7.5-7.8(5H, m), 7.92 (1H, d, J=8 Hz), 8.24 (1H, d, J=8 Hz), 10.31 (1H, br s),10.91 (1H, br s).

Example 765-[4-[(Benzofuran-2-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

Benzofuran-2-carboxylic acid (31 mg, 0.189 mmol) was made into acidchloride in a conventional manner. By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (40mg, 0.126 mmol) obtained in Example 1, and benzofuran-2-carboxylic acidchloride mentioned above, the title compound (59 mg, yield 100%) wasobtained in the same manner as that of Example 1.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.16 (1H, d, J=12 Hz), 3.72 (1H, d, J=12Hz), 7.01 (1H, d, J=9 Hz), 7.23 (2H, d, J=9 Hz), 7.36 (1H, t, J=8 Hz),7.50 (1H, t, J=8 Hz), 7.5-7.8 (4H, m), 7.8-8.0 (5H, m), 8.25 (1H, d, J=8Hz), 10.69 (1H, s), 10.93 (1H, s).

Example 775-[4-[(1-Methyl-1H-indol-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

1-Methyl-1H-indole-3-carboxylic acid (55 mg, 0.314 mmol) was made intoacid chloride in a conventional manner. By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (50mg, 0.158 mmol) obtained in Example 1, and1-methyl-1H-indole-3-carboxylic acid chloride mentioned above, the titlecompound (11 mg, yield 15%) was obtained in the same manner as that ofExample 1.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.16 (1H, d, J=12 Hz), 3.71 (1H, d, J=12Hz), 3.89 (3H, s), 7.04 (1H, d, 7.1-7.3 (4H, m), 7.5-7.8 (4H, m),7.8-7.9 (2H, m), 7.93 (1H, d, J=8 Hz), 8.20 (1H, d, J=7 Hz), 8.2-8.3(2H, m), 9.90 (1H, s), 10.93 (1H, s).

Example 785-[4-(2-Propenylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

5-[4-(2-Iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(70 mg, 0.128 mmol), allyltributyltin (98 mg, 0.32 mmol), andtetrakistriphenylphosphine palladium(O) (15 mg, 12.8 μmol) weredissolved in anhydrous toluene (0.6 mL), and the solution was stirred at110° C. for 16 hours. The reaction mixture was left to cool, and thenadded with acetonitrile, the mixture was washed with petroleum ether,and the solvent of the acetonitrile layer was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (chloroform/methanol=10011) to obtain the title compound(40 mg, yield 68%).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.54 (2H, d, J=6Hz), 3.70 (1H, d, J=12 Hz), 4.9-5.1 (2H, m), 5.8-6.0 (1H, m), 7.02 (1H,d, J=9 Hz), 7.19 (2H, d, J=9 Hz), 7.3-7.4 (2H, m), 7.4-7.5 (2H, In),7.59 (1H, t, J=8 Hz), 7.6-7.7 (2H, m), 7.79 (2H, d, J=9 Hz), 7.92 (1H,d, J=7 Hz), 8.25 (1H, d, J-=9 Hz), 10.47 (1H, s), 10.86 (1H, br s).

Example 795-[4-(2-Propylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

5-[4-(2-Propenylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(30 mg, 0.065 mmol) was dissolved in a mixture of methanol (0.3 mL) andtetrahydrofuran (0.3 mL), the atmosphere was substituted with argon,then the solution was added with 10% palladiumcarbon (3 mg), and themixture was stirred for 16 hours under a hydrogen atmosphere. Aftercompletion of the reaction, the reaction mixture was filtered throughCelite, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(chloroform/methanol=100/1) to give the title compound (14 mg, yield46%).

¹H NMR (DMSO-de; 400 MHz) δ: 0.86 (3H, t, J=7 Hz), 1.58 (2H, q, J=7 Hz),2.71 (2H, t, J=7 Hz), 3.15 (1H, d, J=12 Hz), 3.70 (ill, d, J=12 Hz),7.02 (1H, d, J=9 Hz), 7.20 (2H, d, J=9 Hz), 7.31 (2H, d, J=8 Hz),7.3-7.5 (2H, m), 7.59 (1H, t, J=8 Hz), 7.6-7.7 (2H, m), 7.79 (2H, d, J=9Hz), 7.92 (1H, d, J=8 Hz), 8.25 (1H, el, J=8 Hz), 10.46 (1H, s), 10.88(1H, br s).

Example 805-[3-Fluoro-4-(2-iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-amino-3-fluorophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(30 mg, 0.09 mmol) synthesized in the same manner as that of Example 1,(3), and 2-iodobenzoyl chloride (0.134 mmol), the title compound (19 mg,yield 38%) was obtained in the same manner as that of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.17 (1H, d, J=12 Hz), 3.71 (1H, d, J=12Hz), 7.00 (1H, d, J=9 Hz), 7.07 (1H, d, J=9 Hz), 7.2-7.3 (1H, m), 7.37(1H, d, J=11 Hz), 7.49 (2H, s), 7.6-7.8 (3H, m), 7.8-8.0 (3H, m), 8.27(1H, d, J=8 Hz), 10.40 (1H, s), 10.90 (1H, s).

Example 815-[4-(2-Hydroxy-3-methylbenzoyl)aminophenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,4]diazepine-2,4(3H,5H)-dione

5-[4-(2-Methoxy-3-methylbenzoyl)aminophenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(24 mg, 0.051 mmol) obtained in Example 61 was treated with a 1 Msolution of boron tribromide in dichloromethane in the same manner asthat of Example 23 to give the title compound (10 mg, yield 43%) aswhite crystals.

¹H NMR (DMSO-d₆, 400 MHz) δ: 1.6-1.9 (4H, m), 2.19 (3H, s), 2.5-2.8 (3H,m), 2.9-3.0 (1H, m), 3.04 (1H, d, J=12 Hz), 3.57 (1H, d, J=12 Hz), 6.66(1H, d, J=8 Hz), 6.8-6.9 (2H, m), 7.17 (2H, d, J=9 Hz), 7.37 (1H, d, J=7Hz), 7.74 (2H, d, J=9 Hz), 7.90 (1H, d, J=8 Hz), 9.89 (1H, s), 10.53(1H, br s), 12.44 (1H, s).

5-[4-[(2-Isopropoxybenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

2-Isopropoxybenzoic acid (36 mg, 0.2 mmol) was treated with thionylchloride in the same manner as that of Example 13, and then by using theresultant together with5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32mg, 0.1 mmol), the title compound (36 mg, yield 75%) was obtained aswhite crystals in the same manner as that of Example 1, (4).

¹H NMR (DMSO-da, 400 MHz) δ: 1.37 (6H, d, J=6 Hz), 3.16 (1H, d, J=1.2Hz), 3.71 (1H, d, J=12 Hz), 4.7-4.8 (1H, m), 7.0-7.1 (2H, m), 7.2-7.3(3H, m), 7.50 (1H, t, J=7 Hz), 7.60 (1H, t, J==7 Hz), 7.6-7.8 (2H, m),7.78 (2H, d, J=9 Hz), 7.93 (1H, d, J=8 Hz), 8.26 (1H, d, J=8 Hz), 10.27(1H, s), 10.91 (1H, s).

Example 835-[4-[(3-Methylthiophen-2-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

3-Methyl-2-thiophenecarboxylic acid (28 mg, 0.2 mmol) was treated withthionyl chloride in the same manner as that of Example 13, and then byusing the resultant together with5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32mg, 0.1 mmol) obtained in Example 1, (3), the title compound (42 mg,yield 95%) was obtained as white crystals in the same manner as that ofExample 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 2.46 (3H, s), 3.16 (1H, d, J=12 Hz), 3.70(1H, d, J=1.2 Hz), 7.0-7.1 (2H, m), 7.20 (2H, d, J=9 Hz), 7.60 (1H, t,J=7 Hz), 7.6-7.8 (3H, m), 7.75 (2H, d, J-=9 Hz), 7.92 (1H, d, d=8 Hz),8.26 (1H, d, J=8 Hz), 10.11 (1H, s), 10.90 (1H, s).

Example 845-[4-(2-Phenoxypropionylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

2-Phenoxypropionic acid (32 mg, 0.193 mmol) was made into acid chloridein a conventional manner. By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30mg, 0.095 mmol) obtained in Example 1, (3), and 2-phenoxypropionic acidchloride mentioned above, the title compound (39 mg, yield 88%) wasobtained in the same manner as that of Example 1.

¹H NMR (DMSO-d₆, 400 MHz) δ: 1.56 (3H, d, J=7 Hz), 3.14 (1H, d, J=12Hz), 3.68 (1H, d, J=12 Hz), 4.87 (1H, q, J=7 Hz), 6.9-7.0 (4H, m), 7.17(2H, d, J=9 Hz), 7.2-7.4 (2H, m), 7.5-7.7 (5H, m), 7.91 (1H, d, J=8 Hz),8.25 (1H, d, J=9 Hz), 10.27 (1H, s), 10.88 (1H, br s).

Example 855-[4-[2-(4-Chloro-2-methylphenoxy)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

(4-Chloro-2-methylphenoxy)acetic acid (38 mg, 0.189 mmol) was made intoacid chloride in a conventional manner. By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30mg, 0.095 mmol) obtained in Example 1, and(4-chloro-2-methylphenoxy)acetic acid chloride mentioned above, thetitle compound (47 mg, yield 99%) was obtained in the same manner asthat of Example 1.

¹H NMR (DMSO-d₆, 400 MHz) δ: 2.24 (3H, s), 3.15 (1H, d, J=12 Hz), 3.69(1H, d, J=12 Hz), 4.74 (2H, s), 6.89 (1H, d, J=9 Hz), 6.99 (1H, d, J=9Hz), 7.1-7.3 (4H, m), 7.59 (1H, t, J=8 Hz), 7.5-7.7 (5H, m), 7.91 (1H,d, J=8 Hz), 8.25 (1H, d, J=8 Hz), 10.22 (1H, s), 10.88 (1H, br s).

Example 865-[4-(4-Fluoro-2-trifluoromethylbenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 1, (3), and 4-fluoro-2-(trifluoromethyl)benzoylchloride, the title compound (yield 52%) was obtained in the same manneras that of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.70 (1H, d, J=12Hz), 7.01 (1H, d, J=9 Hz), 7.22 (2H, d, J=9 Hz), 7.5-7.9 (8H, m), 7.91(1H, d, J=8 Hz), 8.24 (1H, d, J=8 Hz), 10.72 (1H, s), 10.88 (1H, br s).

Example 875-[4-(4-Fluoro-2-methoxybenzoyl)amino-phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 1, (3), and 4-fluoro-2-methoxybenzoyl chloride, thetitle compound (yield 62%) was obtained in the same manner as that ofExample 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.69 (1H, d, J=12Hz), 3.90 (3H, s), 6.89 (1H, dt, J=2 Hz, 9 Hz), 7.01 (1H, d, J=9 Hz),7.09 (1H, dd, J=2 Hz, 9 Hz), 7.19 (2H, d, J=8 Hz), 7.5-7.7 (3H, m), 7.77(2H, d, J=9 Hz), 7.91 (1H, d, J=8 Hz), 8.24 (1H, d, J=9 Hz), 10.18 (1H,s), 10.88 (1H, br s).

Example 885-[4-(4-Fluoro-2-hydrooxybenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-[4-(4-fluoro-2-methoxybenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 87, the title compound (yield 49%) was obtained inthe same manner as that of Example 18.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.71. (1H, d, J=12Hz), 6.7-6.9 (2H, m), 7.01 (1H, d, J=9 Hz), 7.23 (2H, d, J=9 Hz), 7.59(1H, t, J=7 Hz), 7.65 (1H, d, J=7 Hz), 7.69 (1H, d, J=9 Hz), 7.76 (1H,d, J=9 Hz), 7.91 (1H, d, J=8 Hz), 8.01 (1H, t, J=8 Hz), 8.25 (1H, d, J=9Hz), 10.50 (1H, br s), 10.89 (1H, s).

Example 895-[3-[(2-Iodophenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

2-Iodophenylacetic acid (39 mg, 0.15 mmol) was treated with thionylchloride in the same manner as that of Example 13, and then by using theresultant together with5-(3-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32mg, 0.1 mmol) obtained in Example 53, (1), the title compound (13 mg,yield 23%) was obtained as pale brown powder in the same manner as thatof Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.14 (1H, d, J=12 Hz), 3.72 (1H, d, J=12Hz), 3.79 (213, s), 7.0-7.1 (3H, m), 7.3-7.5 (3H, m), 7.47 (1H, s),7.5-7.7 (4H, m), 7.82 (1H, d, J=8 Hz), 7.92 (1H, d, J=9 Hz), 8.24 (1H,d, J=9 Hz), 10.33 (1H, s), 10.90 (1H, s).

Example 905-[4-(2-Methyl-2-phenoxypropionylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

2-Methyl-2-phenoxypropionic acid (34 mg, 0.189 mmol) was made into acidchloride in a conventional manner. By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30mg, 0.095 mmol) obtained in Example 1, (3), and2-methyl-2-phenoxypropionic acid chloride mentioned above, the titlecompound (46 mg, yield 100%) was obtained in the same manner as that ofExample 1.

¹H NMR (DMSO-d₆, 400 MHz) δ: 1.54 (6H, s), 3.15 (1H, d, J=12 Hz), 3.69(1H, d, J=12 Hz), 6.93 (2H, d, J=9 Hz), 6.9-7.1 (2H, m), 7.16 (2H, d,J=9 Hz), 7.2-7.4 (2H, m), 7.59 (1H, t, J=8 Hz), 7.5-7.7 (3H, m), 7.76(2H, d, 7.91 (1H, d, J=8 Hz), 8.25 (1H, d, J=8 Hz), 10.16 (1H, s), 10.88(1H, br s).

Example 915-[4-(2-tert-Butylbenzoylamino)phenyl]-1,3-dihydronaphtho[1,2-e]-1,4-diazepin-2-one

2-tert-Butylbenzoic acid (24 mg, 0.135 mmol) was made into acid chloridein a conventional manner. By using5-(4-aminophenyl)-1,3-dihydronaphtho[1,2-e]-1,4-diazepin-2-one (20 mg,0.066 mmol) obtained in Example 64, and 2-tert-butylbenzoyl chloride (24mg, 0.135 mmol) mentioned above, the title compound (30 mg, yield 99%)was obtained in the same manner as that of Example 1.

¹H NMR (DMSO-d₆, 400 Hz) δ: 1.39 (9H, s), 3.78 (1H, d, J=10 Hz), 4.56(1H, d, J=10 Hz), 7.2-7.4 (3H, m), 7.3-7.5 (1H, m), 7.54 (3H, d, J=9Hz), 7.6-7.8 (5H, m), 8.0-8.1 (1H, m), 8.3-8.4 (1H, m), 10.61 (1H, s),10.81 (1H, s).

Example 925-[4-[(3-Dimethylaminobenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

3-Dimethylaminobenzoic acid (50 mg, 0.3 mmol) was treated oxalylchloride with in the same manner as that of Example 40, and then byusing the resultant together with5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32mg, 0.1 mmol) obtained in Example 1, (3), the title compound (17 mg,yield 37%) was obtained as pale brown crystals in the same manner asthat of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 2.97 (6H, s), 3.16 (1H, d, J=12 Hz), 3.70(1H, d, J=12 Hz), 6.93 (1H, d, J=9 Hz), 7.02 (1H, d, J=9 Hz), 7.1-7.3(4H, m), 7.32 (1H, t, J=8 Hz), 7.60 (1H, t, J=7 Hz), 7.66 (1H, d, J=7Hz), 7.70 (1H, d, J=9 Hz), 7.84 (2H, d, J=9 Hz), 7.92 (1H, d, J=8 Hz),8.26 (1H, d, J=8 Hz), 10.25 (1H, s), 10.89 (1H, s).

5-[4-(4-Iodo-2-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 1, (3), and 4-iodo-2-methoxybenzoyl chloride, thetitle compound (yield 93%) was obtained in the same manner as that ofExample 1, (4).

¹H NMR (DMSO-dc, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.69 (1H, d, J=12Hz), 3.89 (3H, s), 7.00 (1H, d, J=9 Hz), 7.19 (2H, d., J=9 Hz), 7.35(1H, d, J=8 Hz), 7.44 (1H, d, J=8 Hz), 7.51 (1H, s), 7.58 (1H, t, J=7Hz), 7.6-7.7 (2H, m), 7.76 (2H, d, J=9 Hz), 7.91 (1H, d, J=8 Hz), 8.24(1H, d, J=8 Hz), 10.22 (1H, br s), 10.88 (1H, br s).

Example 945-[4-(6-Fluoro-2-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 1, (3), and 2-fluoro-6-methoxybenzoyl chloride, thetitle compound (yield 78%) was obtained in the same manner as that ofExample 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.70 (1H, d, J=12Hz), 3.82 (3H, a), 6.90 (1H, t, J=8 Hz), 6.98 (1H, d, J=8 Hz), 7.01 (1H,d, J=9 Hz), 7.20 (2H, el, J=9 Hz), 7.4-7.5 (1H, m), 7.59 (1H, t, J=7Hz), 7.6-7.7 (2H, m), 7.75 (2H, d, J=9 Hz), 7.92 (1H, d, J=8 Hz), 8.24(1H, d, J=8 Hz), 10.64 (1H, s), 10.88 (1H, br s).

Example 955-[4-(2-Hydroxy-4-iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-[4-(4-iodo-2-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 93, the title compound (yield 26%) was obtained inthe same manner as that of Example 18.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.70 (1H, d, J=12Hz), 7.00 (1H, d, J=9 Hz), 7.22 (2H, d, J=9 Hz), 7.33 (1H, dd, J=2 Hz, 8Hz), 7.37 (1H, d, J=2 Hz), 7.5-7.7 (4H, m), 7.76 (2H, d, J=9 Hz), 7.91(1H, d, J=8 Hz), 8.25 (1H, d, J=8 Hz), 10.43 (1H, s), 10.89 (1H, s),11.82 (1H, br s).

5-[4-(6-Fluoro-2-hydroxyamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-[4-(6-fluoro-2-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 94, the title compound (yield 98%)) was obtained inthe same manner as that of Example 18.

¹H NMR (DMSO-d₆, 400 Hz) δ: 3.15 (1H, d, J=12 Hz), 3.70 (1H, d, 6.70(1H, t, J=9 Hz), 6.75 (1H, d, J=8 Hz), 7.01 (1H, d, J=9 Hz), 7.19 (2H,d, J=9 Hz), 7.2-7.3 (1H, m), 7.58 (1H, t, J=7 Hz), 7.6-7.7 (2H, m), 7.76(2H, d, J=9 Hz), 7.91 (1H, d, J=8 Hz), 8.25 (1H, d, J=9 Hz), 10.34 (1H,br s), 10.57 (1H, s), 10.88 (1H, s).

Example 975-[4-(2-Fluorobenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32mg, 0.101 mmol) obtained in Example 1, (3), and 2-fluorobenzoyl chloride(32 mg, 0.202 mmol), the title compound (30 mg, yield 67%) was obtainedas white crystals in the same manner as that of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.72 (1H, d, J=12Hz), 7.03 (1H, d, J=9 Hz,), (4H, m), 7.5-7.7 (5H, m), 7.79 (2H, d, J=9Hz), 7.93 (1H, d, J=8 Hz), 8.25 (1H, d, J=8 Hz), 10.59 (1H, s), 10.93(1H, s).

Example 985-[4-[(2-Dimethylaminobenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

2-Dimethylaminobenzoic acid (50 mg, 0.3 mmol) was treated with oxalylchloride in the same manner as that of Example 40, and then by using theresultant together with5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32mg, 0.1 mmol) obtained in Example 1, (3), the title compound (38 mg,yield 82%) was obtained as pale yellow crystals in the same manner asthat of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 2.79 (6H, s), 3.16 (1H, d, J=12 Hz), 3.71(1H, d, J=0.12 Hz), 7.04 (1H, d, J=9 Hz), 7.09 (1H, t, J=8 Hz), 7.2-7.3(3H, m), 7.46 (1H, dt, J=0.2 Hz, 8 Hz), 7.60 (1H, t, J=7 Hz), 7.6-7.8(3H, m), 7.80 (2H, d, J-=8 Hz), 7.93 (1H, d, J=8 Hz), 8.26 (1H, d, J=9Hz), 10.89 (1H, s), 11.37 (1H, s).

Example 995-[4-(2-Methoxy-6-methylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 1, (3), and 2-methoxy-6-methylbenzoyl chloride, thetitle compound (yield 61%) was obtained in the same manner as that ofExample 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 2.23 (3H, s), 3.15 (1H, d, J=12 Hz), 3.70(1H, d, J=12 Hz), 3.76 (3H, s), 6.87 (1H, d, J=8 Hz), 6.94 (1H, d, J=9Hz), 7.03 (1H, d, 7.18 (2H, d, J=8 Hz), 7.29 (1H, t, J=8 Hz), 7.5-7.7(3H, m), 7.78 (2H, d, J=8 Hz), 7.92 (1H, d, J=8 Hz), 8.25 (1H, d, J=9Hz), 10.43 (1H, br s), 10.87 (1H, br s).

Example 1005-[4-(2-Hydroxy-6-methylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-[4-(2-methoxy-6-methylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione,the title compound (yield 67%) was obtained in the same manner as thatof Example 18.

¹H NMR (DMSO-d₆, 400 MHz) δ: 2.22 (3H, s), 3.15 (1H, d, J=12 Hz), 3.69(1H, d, J=12 Hz), 6.68 (1H, d, J=7 Hz), 6.73 (1H, d, J=8 Hz), 7.02 (1H,(1, J=9 Hz), 7.10 (1H, t, J=8 Hz), 7.17 (2H, d, J=9 Hz), 7.58 (1H, t,J=8 Hz), 7.66 (1H, t, J=7 Hz), 7.69 (1H, d, J=911 z), 7.79 (2H, d, J=9Hz), 7.91 (1H, d, J=8 Hz), 8.25 (1H, d, J=9 Hz), 9.65 (1H, br s), 10.37(1H, br s), 10.87 (1H, br s).

Example 1015-[4-[3-(2-Methylphenyl)propionylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30mg, 0.095 mmol) obtained in Example 1, (3), and3-(2-methylphenyl)propionic acid chloride (0.114 mmol), the titlecompound (28 mg, yield 64%) was obtained as white crystals in the samemanner as that of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 2.29 (3H, s), 2.58 (2H, t, J=8 Hz), 2.88(2H, t, 3.12 (1H, d, J=12 Hz), 3.67 (1H, d, J=12 Hz), 6.97 (1H, d, J=9Hz), 7.0-7.2 (6H, m), 7.5-7.7 (5H, m), 7.90 (1H, d, J=8 Hz), 8.23 (1H,d, J=8 Hz), 10.07 (1H, br s), 10.89 (1H, br s).

Example 1025-(4-Phenylcarbamoylphenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(1) Ethyl 4-(1-aminonaphthalen-2-ylamino)benzoate

By using ethyl 4-(1-nitronaphthalen-2-ylamino)benzoate, the titlecompound was obtained in the same manner as that of Example 1, (2).

¹H NMR (CDCl₃, 400 MHz) δ: 1.35 (3H, t, J=7 Hz), 4.32 (2H, q, J=7 Hz),4.36 (2H, br s), 5.62 (1H, br s), 6.66 (2H, d, J=9 Hz), 7.2-7.4 (2H, m),7.4-7.6 (2H, m), 7.8-7.9 (4H, m).

(2) Ethyl 4-[1-(3-ethoxy-3-oxopropanamido)naphthalen-2-ylamino]benzoate

By using ethyl 4-(1-aminonaphthalen-2-ylamino)benzoate, the titlecompound was obtained in the same manner as that of Example 1, (3).

¹H NMR (CDCl₃, 400 MHz) δ: 1.36 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz),3.66 (2H, s), 4.33 (2H, q, J=7 Hz), 4.33 (2H, q, J=7 Hz), 6.9-7.0 (2H,m), 7.06 (1H, s), 7.45 (1H, t, J=7 Hz), 7.56 (1H, dt, J=1 Hz, 8 Hz),7.63 (1H, d, J=9 Hz), 7.78 (1H, d, J=9 Hz), 7.84 (1E, d, J=8 Hz), 7.91(2H, d, J=8 Hz), 7.96 (1H, d, J=8 Hz), 9.62 (1H, s).

(3) Ethyl4-[2,4-dioxo-3,4-dihydro-1H-naphtho[2,1-b][1,4]diazepin-5(2H)-yl]benzoate

By using ethyl4-[1-(3-ethoxy-3-oxopropanamido)naphthalen-2-ylamino]benzoate, the titlecompound was obtained in the same manner as that of Example 1, (3).

¹H NMR (CDCl₃, 400 MHz) δ: 1.39 (3H, t, J=7 Hz), 3.63 (2H, s), 4.39 (2H,q, J=7 Hz), 6.96 (1H, d, J=9 Hz), 7.3-7.4 (2H, m), 7.5-7.8 (3H, m), 7.87(1H, d, J=8 Hz), 8.0-8.2 (3H, m), 8.68 (1H, s).

(4) 4-[2,4-Dioxo-3,4-dihydro-1H-naphtho[2,1-b][1,4]diazepin-5(2H)-yl]benzoic acid

Ethyl4-[2,4-Dioxo-3,4-dihydro-1H-naphtho[2,1-b][1,4]diazepin-5(2H)-yl]benzoate(1.19 g, 3.18 mmol) obtained in Example 102, (3), and 8 N aqueous sodiumhydroxide (1.00 mL, 8.00 mmol) were stirred at room temperature inethanol (10 mL) and water (5 mL). After the disappearance of thestarting materials was confirmed, a post-treatment was performed in aconventional manner to obtain the title compound (905 mg, yield 82%).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.17 (1H, d, J=12 Hz), 3.75 (1H, d, J=12Hz), 6.95 (1H, d, J=9 Hz), 7.35 (2H, d, J=9 Hz), 7.5-7.8 (3H, m), 7.93(1H, d, J=8 Hz), 7.99 (2H, d, J=0.9 Hz), 8.27 (1H, d, J=8 Hz), 10.93(1H, s).

(5)5-(4-Phenylcarbamoylphenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

4-[2,4-Dioxo-3,4-dihydro-1H-naphtho[2,1-b][1,4]diazepin-5(2H)-yl]benzoic acid (50 mg, 0.144 mmol) obtained in Example 102, (4),WSC.HCl (39 mg, 0.202 mmol), HOBt (31 mg, 0,202 mmol),N-methylmorpholine (47 μL, 0.432 mmol), and aniline (14 μL, 0.158 mmol)were stirred at room temperature for 16 hours in anhydrous DMF (1.5 mL).The reaction mixture was post-treated in a conventional manner to givethe title compound (30 mg, yield 49%).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.18 (1H, d, J=12 Hz), 3.75 (1H, d, J=12Hz), 6.98 (1H, d, J=9 Hz), 7.10 (1H, t, J=7 Hz), 7.3-7.4 (4H, m),7.5-7.8 (5H, m), 7.93 (1H, d, J=8 Hz), 8.01 (2H, d, J=8 Hz), 8.27 (1H,d, J=8 Hz), 10.30 (1H, br s), 10.93 (1H, br s).

Example 1035-(4-Benzylcarbamoylphenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using 4-[2,4-dioxo-3,4-dihydro-1H-naphtho[2,1-b][1,4]diazepin-5(2H)-yl]benzoic acid obtained in Example 102, (4), and benzylamine, thetitle compound (yield 56%) was obtained in the same manner as that ofExample 102, (5),

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.16 (1H, d, J=0.12 Hz), 3.74 (1H, d, J=12Hz), 4.48 (2H, d, J=6 Hz), 6.95 (1H, d, J=9 Hz), 7.2-7.4 (7H, m),7.5-7.7 (3H, m), 7.9-8.0 (3H, m), 8.27 (1H, d, J=8 Hz), 9.09 (1H, t, J=6Hz), 10.91 (1H, br s).

Example 1045-[4-[3-(2-Methylphenyl)propenoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30mg, 0.095 mmol) obtained in Example 1, (3), and 2-methylcinnamic acidchloride (0.114 mmol), the title compound (18 mg, yield 41%) wasobtained as white crystals in the same manner as that of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 2.42 (3H, s), 3.17 (1H, d, J=12 Hz), 3.71(1H, d, J=12 Hz), 6.80 (1H, d, J=16 Hz), 7.02 (1H, d, J=9 Hz), 7.20 (2H,d, J=8 Hz), 7.2-7.3 (3H, m), 7.6-7.7 (4H, m), 7.7-7.9 (3H, m), 7.92 (1H,d, J=8 Hz), 8.26 (1H, d, J=8 Hz), 10.50 (1H, br s), 10.93 (1H, br s).

5-[4-[(3-(2-Chlorophenyl)propionylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 1, (3) (35 mg, 0.110 mmol), and3-(2-chlorophenyl)propionic acid chloride (0.132 mmol), the titlecompound (30 mg, yield 56%) was obtained as white crystals in the samemanner as that of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) 5.2.67 (2H, t, J=8 Hz), 3.03 (2H, t, J=8 Hz),3.14 (1H, d, J=12 Hz), 3.70 (1H, d, J=12 Hz), 6.98 (1H, d, J=9 Hz), 7.16(2H, d, J=9 Hz), 7.2-7.3 (2H, m), 7.3-7.4 (1H, m), 7.4-7.5 (1H, m),7.5-7.7 (5H, m), 7.92 (1H, d, J=8 Hz), 8.22 (1H, d, J=8 Hz), 10.16 (1H,br s), 10.92 (1H, br

Example 1065-[4-(2-Iodobenzoyl)aminophenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

2-Iodobenzoic acid (74 mg, 0.3 mmol) was treated with thionyl chloridein the same manner as that of Example 13, and then by using theresultant together with5-(4-aminophenyl)-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(64 mg, 0.2 mmol) obtained in Example 55, (6), the title compound (45mg, yield 41%) was obtained as off-white crystals in the same manner asthat of Example 1, (4).

¹H NMR (HMSO-d₆, 400 MHz) δ: 1.6-1.9 (4H, In), 2.5-2.8 (3H, m), 2.8-3.0(1H, m), 3.04 (1H, J=12 Hz), 3.56 (1H, d, J=12 Hz), 6.66 (1H, d, J=8Hz), 6.88 (1H, J=8 Hz), 7.14 (2H, d, J=9 Hz), 7.23 (1H, ddd, J=2 Hz, 7Hz, 8 Hz), 7.4-7.6 (2H, m), 7.54 (2H, d, J=9 Hz), 7.93 (1H, d, J=8 Hz),9.86 (1H, s), 10.52 (1H, s).

Example 107

5-[4-[(1-Methyl-1H-pyrrol-2-ylacetyl)amino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione1-Methylpyrrole-2-acetic acid (14 mg, 0.1 mmol),5-(4-aminophenyl)-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(31-1,5M-dione(16 mg, 0.05 mmol) obtained in Example 55, (6), dimethylformamide (1mL), 1-hydroxybenzotriazole monohydrate (14 mg, 0.1 mmol), and1-ethyl-3-(3-dimethylaminopropypcarbodiirnide hydrochloride (19 mg, 0.1mmol) were mixed, and the mixture was stirred at room temperature for 24hours. This reaction mixture was added with water, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated aqueous sodium hydrogencarbonate, then washed with saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (methanol/chloroform=1/50), and thenwashed with ethyl acetate to give the title compound (6 mg, yield 28%)as slightly brown crystals.

¹H NMR (DMSO-d₆, 400 MHz) δ: 1.6-1.9 (4H, m), 2.5-2.8 (3H, m), 2.8-3.0(1H, m), 3.02 (1H, d, J=12 Hz), 3.54 (1H, d, J=12 Hz), 3.56 (3H, s),3.64 (2H, s), 5.8-6.0 (2H, m), 6.6-6.7 (2H, m), 6.86 (1H, d, J=8 Hz),7.08 (2H, d, J=9 Hz), 7.61 (2H, d, J=9 Hz), 9.85 (1H, s), 10.16 (1H, s).

Example 1085-[4-(2-Chlorobenzyl)carbamoylphenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using4-[2,4-dioxo-3,4-dihydro-1H-naphtho[2,1-b][1,4]diazepin-5(2H)-yl]benzoicacid obtained in Example 102, (4), and 2-chlorobenzylamine, the titlecompound (yield 15%) was obtained in the same manner as that of Example102, (5).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.17 (1H, d, J=12 Hz), 3.74 (1H, d, J=12Hz), 4.54 (2H, d, J=6 Hz), 6.96 (1H, d, J=9 Hz), 7.2-7.7 (9H, m), 7.92(1H, d, J=7 Hz), 7.97 (2H, d, J=9 Hz), 8.27 (1H, d, J=8 Hz), 9.09 (1H,t, J=6 Hz), 10.91 (1H, br s).

Example 1095-[4-[3-(2-Chlorophenyl)propenoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl.)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 1, (3) (40 mg, 0.126 mmol), and 2-chlorocinnamicacid chloride (0,151 mmol), the title compound (30 mg, yield 50%) wasobtained as white crystals in the same manner as that of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.17 (1H, d, J=12 Hz), 3.71 (1H, d, J=12Hz), 6.9-7.1 (2H, m), 7.21 (2H, d, J=9 Hz), 7.4-7.5 (2H, m), 7.5-7.6(2H, m), 7.6-7.7 (2H, m), 7.80 (3H, t, J=9 Hz), 7.8-7.9 (2H, m), 8.26(1H, d, J=8 Hz), 10.72 (1H, br s), 10.94 (1H, br s).

Example 1105-[4-(2-Chlorophenyl)carbamoylphenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using 4-[2,4-dioxo-3,4-dihydro-1H-naphtho[2,1-b][1,4]diazepin-5(2H)-yl]benzoic acid obtained in Example 102, (4), and 2-chloroaniline,the title compound (yield 15%) was obtained in the same manner as thatof Example 102, (5).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.18 (1H, d, J=12 Hz), 3.76 (1H, d, J=12Hz), 6.99 (1H, d, J=9 Hz), 7.30 (1H, t, J=8 Hz), 7.3-7.8 (8H, m), 723(1H, d, J=8 Hz), 8.05 (2H, d, J=8 Hz), 8.28 (1H, d, J=8 Hz), 10.13 (1H,br s), 10.93 (1H, br s).

Example 1115-[4-(6-Bromo-2,3-methylenedioxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 1, (3), and 5-bromo-1,3-benzodioxol-4-carbonylchloride, the title compound (yield 64%) was obtained in the same manneras that of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.70 (1H, d, J=12Hz), 6.13 (2H, a), 6.98 (1H, d, J=8 Hz), 7.01 (1H, d, J=9 Hz), 7.16 (1H,d, J=8 Hz), 7.22 (2H, d, J=9 Hz), 7.5-7.8 (5H, m), 7.92 (1H, d, J=8 Hz),8.25 (1H, d, J=9 Hz), 10.77 (1H, br s), 10.87 (1H, br s).

Example 1125-[4-(6-Bromo-2-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 1, (3), and 2-bromo-6-methoxybenzoyl chloride, thetitle compound (yield 76%) was obtained in the same manner as that ofExample 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.70 (1H, d, J=12Hz), 3.81 (3H, s), 7.03 (1H, d, J=9 Hz), 7.15 (1H, d, J=8 Hz), 7.19 (2H,d, J=8 Hz), 7.25 (1H, d, J=8 Hz), 7.36 (1H, t, J=9 Hz), 7.59 (1H, t, J=7Hz), 7.6-7.8 (4H, m), 7.92 (1H, d, 8.25 (1H, d, J=9 Hz), 10.60 (1H, brs), 10.88 (1H, br s).

Example 1135-[4-[(2-tert-Butylbenzoyl)amino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

2-tert-Butyl benzoate (43 mg, 0.24 mmol) was treated with thionylchloride in the same manner as that of Example 13, and then by using theresultant together with5-(4-aminophenyl)-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(64 mg, 0.2 mmol) obtained in Example 55, (6), the title compound (81mg, yield 85%) was obtained as slightly brown crystals in the samemanner as that of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 1.39 (9H, s), 1.6-1.9 (4H, m), 2.5-2.8 (3H,m), 2.8-3.0 (1H, m), 3.04 (1H, d, J=12 Hz), 3.55 (1H, d, J=12 Hz), 6.66(1H, d, J=8 Hz), 6.88 (1H, d, J=9 Hz), 7.12 (2H, d, J=9 Hz), 7.2-7.4(2H, m), 7.40 (1H, dt, 8 Hz), 7.53 (1H, d, J=8 Hz), 7.74 (2H, d, J=9Hz), 9.85 (1H, s), 10.50 (1H, s).

Example 1145-[2-(2-Iodobenzoyl)aminopyridin-5-yl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(1) tert-Butyl5-(2,4-dioxo-3,4-dihydro-1H-naphtho[2,1-b][1,4]diazepin-5(2H)-yl)pyridin-2-ylcarbamate

By using 2-amino-5-nitropyridine as the starting material, the titlecompound was obtained in the same manner as that of Example 42, (1).

¹H NMR (CDCl₃, 400 MHz) δ: 1.49 (9H, s), 3.62 (2H, s), 6.99 (1H, d, J=9Hz), 7.5-7.8 (4H, m), 7.8-8.0 (1H, m), 8.03 (1H, d, J=9 Hz), 8.1-8.2(2H, m), 9.06 (1H, br s).

(2)5-[2-(2-Iodobenzoyl)aminopyridin-5-yl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using tert-butyl5-(2,4-dioxo-3,4-dihydro-1H-naphtho[2,1-b][1,4]diazepin-5(2H)-yl)pyridin-2-ylcarbamateobtained above,5-(6-aminopyridin-3-yl)-1H-naphtho[2,1-b][1,4]diazepine-2,4(3H,5H)-dione(15 mg, 0.047 mmol) obtained in the same manner as that of Example 42,(2), and 2-iodobenzoyl chloride (0.07 mmol), the title compound (3 mg,yield 38%) was obtained in the same manner as that of Example 1, (4).

¹H NMR (CDCl₃, 400 MHz) δ: 3.63 (2H, s), 7.01 (1H, d, J=9 Hz), 7.13 (1H,t, J=8 Hz), 7.42 (1H, t, J=8 Hz), 7.52 (1H, d, J=8 Hz), 7.6-7.7 (2H, m),7.7-7.8 (2H, m), 7.8-8.0 (2H, m), 8.10 (2H, d, J=8 Hz), 8.46 (1H, d, J=9Hz), 8.5-8.7 (2H, m).

5-[4-(6-Bromo-2-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-[4-(6-bromo-2-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 112, the title compound (yield 32%) was obtained inthe same manner as that of Example 18.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.69 (1H, d, J=12Hz), 6.91 (1H, d, J=8 Hz), 7.1-7.2 (2H, m), 7.15 (1H, d, J=8 Hz), 7.19(2H, d, J=9 Hz), 7.58 (1H, t, J=8 Hz), 7.6-7.7 (2H, m), 7.91 (1H, d, J=8Hz), 7.76 (2H, d, J=9 Hz), 8.25 (1H, d, J=9 Hz), 10.24 br s), 10.60 (1H,br s), 10.86 (1H, br s).

Example 1165-[4-(6-Chloro-2-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 1, (3), and 2-chloro-6-methoxybenzoyl chloride, thetitle compound (yield 76%) was obtained in the same manner as that ofExample 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.70 (1H, d, J=12Hz), 3.81 (3H, s), 7.03 (1H, d, J=9 Hz), 7.11 (1H, d, J=8 Hz), 7.12 (1H,d, J=8 Hz), 7.20 (2H, d, J=9 Hz), 7.43 (1H, t, J=8 Hz), 7.59 (1H, t, J=7Hz), 7.66 (1H, t, J=8 Hz), 7.69 (1H, d, J=9 Hz), 7.69 OH, d, J=9 Hz),7.75 (2H, d, J=9 Hz), 7.92 (1H, d, j-=8 Hz), 8.25 (1H, d, J=8 Hz), 10.61(1H, br s), 10.86 (1H, br s).

Example 1175-[4-(2-Iodobenzoylamino)phenyl]-1H-[1,4]diazepino[2,3-h]quinoline-2,4(3H,5H)-dione(1) 5-(4-Aminophenyl)-1H-[1,4]diazepino[2,3-h]quinoline-2,4(3H,5H)-dione

By using 7-hydroxy-8-nitroquinoline as the starting material, the titlecompound was obtained in the same manner as that of Example 42, (1) and(2).

¹H NMR (CDCl₃, 400 MHz) δ: 3.61 (2H, s), 3.81 (2H, br s), 6.69 (2H, d,J=9 Hz), 6.99 (2H, d, J=9 Hz), 7.13 (1H, d, J=9 Hz), 7.45 (2H, d, J=9Hz), 7.50 (1H, dd, J=4 Hz, 8 Hz), 8.12 (1H, dd, J=1 Hz, 8 Hz), 8.91 (1H,dd, J=1 Hz, 4 Hz), 9.51 (1H, br s).

(2)5-[4-(2-Iodobenzoylamino)phenyl]-1H-[1,4]diazepino[2,3-h]quinoline-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-[1,4]diazepino[2,3-h]quinolone-2,4(3H,5H)-dione (30mg, 0.097 mmol) obtained above, and 2-iodobenzoyl chloride (0.14 mmol),the title compound (10 mg, yield 19%) was obtained in the same manner asthat of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.2-3.5 (2H, m), 7.11 (1H, d., J=9 Hz),7.2-7.4 (3H, m), 7.4-7.6 (2H, m), 7.6-7.7 (1H, m), 7.71 (1H, d, J=9 Hz),7.78 (2H, d, J=8 Hz), 7.93 (1H, d, J=8 Hz), 8.39 (1H, d, J=8 Hz), 9.00(1B, d, J=5 Hz), 10.25 (1H, s), 10.56 (1H, s).

Example 1185-[4-(6-Chloro-2-hydroxybenzoylamino)phenyl]1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-[4-(6-chloro-2-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 116, the title compound (yield 80%) was obtained inthe same manner as that of Example 18.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.69 (1H, d, J=12Hz), 6.88 (1H, d, J=8 Hz), 6.92 (1H, d, J=8 Hz), 7.02 (1H, d, J=9 Hz),7.19 (2H, d, J=9 Hz), 7.23 (1H, t, J=8 Hz), 7.59 (1H, t, J=7 Hz),7.6-7.7 (2H, m), 7.76 (2H, d, J=9 Hz), 7.92 (1H, d, J=8 Hz), 8.25 (1H,d, J=9 Hz), 10.25 (1H, br s), 10.62 (1H, br s), 10.87 (1H, br s).

Example 1195-[4-(2-Hydroxy-6-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(1)5-[4-(2,6-Dimethoxybenzoylamino)phenyl]-1H-naphtho[1,2-h][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 1, (3), and 2,6-dimethoxybenzoyl chloride, the titlecompound (yield 71%) was obtained in the same manner as that of Example1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.69 (1H, d, J=12Hz), 3.76 (3H, s), 3.76 (3H, s), 6.73 (2H, d, J=8 Hz), 7.02 (1H, d, J=9Hz), 7.16 (2H, d, J=9 Hz), 7.35 (1H, t, J=8 Hz), 7.5-7.7 (3H, m), 7.76(2H, d, J=9 Hz), 7.92 (1H, d, J=8 Hz), 8.25 (1H, d, J=8 Hz), 10.34 (1H,br s), 10.86 (1H, br s).

(2)5-[4-(2-Hydroxy-6-methoxybenzoylamino)phenyl]-1H-naphtho[1,213]diazepine-2,4(3H,5H)-dione

By using5-[4-(2,6-dimethoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione,the title compound was obtained in the same manner as that of Example18.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.69 (1H, d, J=12Hz), 3.80 (3H, s), 6.53 (1H, d, J=8 Hz), 6.55 (1H, d, J=9 Hz), 7.01 (1H,d, J=9 Hz), 7.18 (2H, d, J=9 Hz), 7.22 (1H, t, J=8 Hz), 7.59 (1H, t, J=7Hz), 7.66 (1H, t, J=7 Hz), 7.69 (1H, d, J=9 Hz), 7.76 (2H, d, J=9 Hz),7.91 (1H, d, J=8 Hz), 8.25 (1H, d, J=8 Hz), 10.36 (1H, br s), 10.65 (1H,br s), 10.87 (1H, br s).

Example 1205-[4-[2-Methoxy-6-(trifluoromethyl)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 1, (3), and 2-methoxy-6-(trifluoromethyl)benzoylchloride, the title compound (yield 74%) was obtained in the same manneras that of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.69 (1H, d, J=12Hz), 3.86 (3H, s), 7.03 (1H, d, J=8 Hz), 7.19 (2H, d, J=9 Hz), 7.36 (1H,d, J=8 Hz), 7.47 (1H, d, J=9 Hz), 7.5-7.8 (6H, m), 7.91 (1H, d, J=9 Hz),8.24 (1H, d, J=8 Hz), 10.61 (1H, br s), 10.87 (1H, br s).

Example 1215-[4-[2-Hydroxy-6-(trifluoromethyl)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-[4-[2-methoxy-6-(trifluoromethyl)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione,the title compound was obtained in the same manner as that of Example18.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.70 (1H, d, J=12Hz), 7.03 (1H, d, J=9 Hz), 7.1-7.3 (4H, m), 7.45 (1H, t, 7.59 t, J=7Hz), 7.6-7.8 (4H, m), 7.92 d, J=7 Hz), 8.25 (1H, d, J=8 Hz), 10.43 (1H,br s), 10.56 (1H, br s), 10.87 (1H, br s).

Example 1225-[4-[(2-Isopropenylbenzoyl)amino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

5-[4-(2-Iodobenzoyl)aminophenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(55 mg, 0.1 mmol) obtained in Example 106, isopropenylboronic acidpinacol ester (20 mg, 0.12 mmol),[1,1′-bis(diphenylphosphino)ferrocene]palladiumdichloride-dichloromethane complex (1:1, 0.8 mg, 1 μmol), cesiumcarbonate (65 mg, 02 mmol), and dry dimethylformamide (1 mL) were mixed,and the mixture was stirred at 90° C. for 16 hours under a nitrogenatmosphere. This reaction mixture was added with water, the mixture wasextracted with ethyl acetate, and the organic layer was washed withsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (methanol/chloroform=1/50), and thenrecrystallized from ethyl acetate/hexane to obtain the title compound (5mg, yield 11%) as pale yellow powder.

¹H NMR (DMSO-d₆, 400 MHz) δ: 1.6-1.9 (4H, m), 2.07 (3H, s), 2.5-2.8 (3H,m), 2.8-3.0 (1H, m), 3.03 (1H, d, J=12 Hz), 3.55 (1H, d, J=12 Hz), 4.97(1H, s), 5.09 (1H, s), 6.65 (1H, J=9 Hz), 6.88 (1H, d, J=9 Hz), 7.10(2H, d, J=9 Hz), 7.3-7.5 (4H, m), 7.70 (2H, 4, J=9 Hz), 9.85 (1H, s),10.34 (1H, s).

Example 1235-[4-[(2-Isopropylbenzoyl)amino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

5-[4-[(2-Isopropenylbenzoyl)amino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(2.0 mg, 43 μmol) obtained in Example 122 was dissolved intetrahydrofuran (1 mL) and methanol (0.5 mL), the solution was addedwith platinum oxide (0.1 mg), and the mixture was stirred at roomtemperature for 24 hours under a hydrogen atmosphere. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (methanol/chloroform=1/100) to give thetitle compound (1.5 mg, yield 74%) as pale brown powder.

¹H NMR (CDCl₃, 400 MHz) δ: 1.28 (6H, d, J=7 Hz), 1.7-2.1 (4H, m),2.5-2.9 (4H, m), 3.39 (1H, m), 3.50 (2H, s), 6.73 (1H, d, J=8 Hz), 6.85(1H, d, J=9 Hz), 7.1-7.3 (4H, m), 7.3-7.6 (5H, m), 7.65 (1H, d, J=8 Hz).

5-[4-[2-Chloro-5-(methylthio)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (50mg, 0.16 mmol) obtained in Example 1, (3), and2-chloro-5-methylthiobenzoyl chloride (0.24 mmol), the title compound(39 mg, yield 49%) was obtained in the same manner as that of Example 1,(4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 2.52 (3H, s), 3.15 (1H, d, J=12 Hz), 3.70(1H, d., J=1.2 Hz), 7.01 (1H, d, J=9 Hz), 7.21 (2H, d, J=9 Hz), 7.3-7.4(1H, m), 7.4-7.5 (2H, m), 7.59 (1H, t, J=8 Hz), 7.6-7.7 (2H, m), 7.77(2H, d, J=9 Hz), 7.92 (1H, d, 8.25 (1H, d, J=8 Hz), 10.64 (1H, s), 10.87(1H, s).

Example 1255-[4-[2-(Methylthio)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30mg, 0.095 mmol) obtained in Example 1, (3), and 2-methylthiobenzoylchloride (0.24 mmol), the title compound (22 mg, yield 20%) was obtainedin the same manner as that of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 2.49 (3H, s), 3.15 (1H, d, J=12 Hz), 3.70(1H, d, J=12 Hz), 7.02 (1H, d, J=9 Hz), 7.20 (2H, d, J=9 Hz), 7.26 (1H,t, J=7 Hz), 7.42 (1H, d, J=7 Hz), 7.4-7.5 (2H, m), 7.59 (1H, t, J=7 Hz),7.6-7.7 (2H, m), 7.78 (2H, (1, J=8 Hz), 7.92 (1H, d, <1=8 Hz), 8.25 (1H,d, J=8 Hz), 10.45 (1H, s), 10.87 (1H, s).

Example 1265-[4-[3-(Methylthio)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30mg, 0.095 mmol) obtained in Example 1, (3), and 3-methylthiobenzoylchloride (0.24 mmol), the title compound (69 mg, yield 92%) was obtainedin the same manner as that of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 2.54 (3H, s), 3.15 (1H, d, J=12 Hz), 3.70(1H, d, J=1.2 Hz), 7.01 (1H, d, J=9 Hz), 7.22 (2H, d, J=4 Hz), 7.4-7.5(2H, m), 7.59 (1H, t, J=8 Hz), 7.6-7.7 (3H, m), 7.7-7.9 (3H, m), 7.91(1H, d, J=8 Hz), 8.25 (1H, d, J=8 Hz), 10.39 (1H, s), 10.88 (1H, s).

Example 1275-[4-[2-Ethyl-6-methoxybenzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (50mg, 0.16 mmol) obtained in Example 1, (3), and 2-ethyl-5-methoxybenzoylchloride (0.24 mmol), the title compound (69 mg, yield 90%) was obtainedin the same manner as that of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 1.16 (3H, t, J=8 Hz), 2.57 (2H, q, J=8 Hz),3.15 (1H, d, J=12 Hz), 3.70 (1H, d, J=12 Hz), 3.77 (3H, s), 6.9-7.0 (2H,m), 7.03 (1H, d, J=9 Hz), 7.18 (2H, d, J=9 Hz), 7.33 (1H, t, J=8 Hz),7.59 (1H, t, J=8 Hz), 7.6-7.7 (2H, m), 7.78 (2H, d, J=9 Hz), 7.92 (1H,d, J=8 Hz), 8.25 (1H, d, J=9 Hz), 10.43 (1H, s), 10.86 (1H, s).

Example 1285-[4-(3-Methanesulfonybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

5-[4-[3-(Methylthio)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(20 mg, 0.043 mmol) obtained in Example 126 was dissolved indimethylformamide (0.4 mL), the solution was added withm-chloroperbenzoic acid (16 mg, 0.065 mmol), and the mixture was stirredat room temperature for 5 minutes. After completion of the reaction, thereaction mixture was added with ethyl acetate, the organic layer waswashed with saturated aqueous sodium hydrogencarbonate, water, andsaturated brine. The solvent of the organic layer was evaporated underreduced pressure, and the obtained residue was purified by silica gelcolumn chromatography (chloroform/methanol=100/1) to give the titlecompound (13 mg, yield 61%).

¹H NMR (CDCl₃, 400 MHz) δ: 3.10 (3H, s), 3.5-3.6 (2H, m), 6.9-7.1 (3H,m), 7.4-7.6 (4H, m), 7.6-7.7 (2H, m), 7.79 (1H, d, J=8 Hz), 8.06 (1H, d,J=7 Hz), 8.16 (1H, d, J=8 Hz), 8.21 (1H, d, J=7 Hz), 8.51 (1H, s), 9.02(1H, by s), 9.44 (1H, In's).

Example 1296-Ethyl-1-[4-(2-iodobenzoyl)aminophenyl]-1-H-1,5-benzodiazepine-2,4(3H,5H)-dione(1) tert-Butyl 4-(2-amino-3-ethylphenylamino)phenylcarbamate

By using tert-butyl 4-(3-ethyl-2-nitrophenylamino)phenylcarbamate, thetitle compound was obtained in the same manner as that of Example 1,(2).

¹H NMR (CDCl₃, 400 MHz) δ: 1.28 (3H, t, J=7 Hz), 1.50 (9H, s), 2.57 (2H,q, J=7 Hz), 3.75 (2H, br s), 5.04 (1H, br s), 6.26 (1H, br s), 6.6-6.8(3H, m), 6.9-7.0 (2H, m), 7.17 (2H, d, J=8 Hz).

(2) Ethyl3-[2-[4-(tert-butoxycarbonylamino)phenylamino]-6-ethylphenylamino]-3-oxopropionate

By using tert-butyl 4-(2-amino-3-ethylphenylamino)phenylcarbamate, thetitle compound was obtained in the same manner as that of Example 1,(3).

¹H NMR, 400 MHz) δ: 1.22 (3H, t, J=7 Hz), 1.32 (3H, t, J=7 Hz), 1.51(9H, s), 2.64 (2H, q, J=7 Hz), 3.53 (2H, s), 4.26 (2H, q, J=7 Hz), 6.21(1H, s), 6.33 (1H, br s), 6.8-6.9 (1H, m), 6.96 (2H, d, J=9 Hz), 7.0-7.3(4H, m), 8.73 (1H, s).

(3) tert-Butyl4-(6-ethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)phenylcarbamate

By using ethyl3-[2-[4-(tert-butoxycarbonylamino)phenylamino]-6-ethylphenylamino]-3-oxopropionate,the title compound was obtained in the same manner as that of Example 1,(3).

¹H NMR (CDCl₃, 400 MHz) δ: 1.30 (3H, t, J=7 Hz), 1.51 (9H, s′), 2.7-2.8(2H, m), 3.49 (2H, s), 6.51 (1H, s), 6.82 (1H, d, J=7 Hz), 7.0-7.2 (4H,m), 7.38 (2H, d, J=9 Hz), 7.48 (1H, s).

(4) 1-(4-Aminophenyl)-6-ethyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione

By using tert-butyl4-(6-ethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)phenylcarbamate,the title compound was obtained in the same manner as that of Example 1,(3).

¹H NMR (DMSO-d₆, 400 MHz) δ: 1.14 (3H, t, <1=7 Hz), 2.64 (1H, dq, J=8Hz, 7 Hz), 2.89 (1H, dq, J=8115, 7 Hz), 3.00 (1H, d, J=12 Hz), 3.46 (1H,d, J=12 Hz), 5.20 (2H, br s), 6.54 (2H, d, J=8 Hz), 6.77 (3H, d, J=8Hz), 7.0-7.1 (2H, m), 9.93 (1H, s).

(5) 6-Ethyl1-[4-(2-iodobenzoyl)aminophenyl]-1H-1,5-benzodiazepine-2,4(3H,5H)-dione

By using1-(4-aminophenyl)-6-ethyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione,and 2-iodobenzoyl chloride, the title compound was obtained in the samemanner as that of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 1.16 (3H, t, J=7 Hz), 2.6-3.0 (2H, m), 3.06(1H, d, J=12 Hz), 3.55 (1H, d, J=12 Hz), 6.77 (1H, d, J=7 Hz), 7.0-7.3(5H, m), 7.4-7.6 (2H, m), 7.75 (2H, d, J=9 Hz), 7.93 (1H, d, J=8 Hz),10.02 (1H, s), 10.53 (1H, s).

Example 1305-[4-[2-Ethyl-6-hydroxybenzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-[4-[2-ethyl-6-methoxybenzoylamino]phenyl]-1H-naphtho[1,2b][1,4]diazepine-2,4(3H,5H)-dione(20 mg, 0.042 mmol) obtained in Example 127, the title compound (12 mg,yield 61%) was obtained in the same manner as that of Example 18.

¹H NMR (DMSO-d₆, 400 MHz) δ: 1.15 (3H, t, J=8 Hz), 2.55 (2H, q, J=8 Hz),3.15 (1H, d, J=12 Hz), 3.69 (1H, d, J=12 Hz), 6.73 (2H, t, J=8 Hz), 7.03(1H, d, J=9 Hz), 7.1-7.2 (3H, m), 7.59 (1H, t, J=8 Hz), 7.6-7.7 (2H, m),7.79 (2H, d, J=9 Hz), 7.92 (1H, d, J=8 Hz), 8.24 (1H, d, J=9 Hz), 9.58(1H, br s), 10.37 (1H, s), 10.86 (1H, br s).

Example 1315-[4-(3-Methanesulfinylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

5-[4-[3-(Methylthio)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(20 mg, 0.043 mmol) obtained in Example 126 was dissolved indimethylformamide (0.4 mL), the solution was added withm-chloroperbenzoic acid (11 mg, 0.03 mmol) at −20° C., and the mixturewas stirred for 30 minutes. After completion of the reaction, thereaction mixture was added with ethyl acetate at −20° C., the organiclayer was washed with saturated aqueous sodium hydrogencarbonate, water,and saturated brine. The solvent of the organic layer was evaporatedunder reduced pressure, and the obtained residue was purified by silicagel column chromatography (chloroform/methanol=100/1) to obtain thetitle compound (8 mg, yield 38%).

¹H NMR (CDCl₃, 400 MHz) δ: 2.77 (3H, s), 3.57 (2H, s), 7.00 (1H, d, J=9Hz), 7.1-7.2 (2H, m), 7.5-7.8 (7H, m), 7.82 (1H, d, J=8 Hz), 8.06 (1H,d, J=7 Hz), 8.15 (1H, d, J=8 Hz), 8.25 (1H, s), 8.92 (1H, br s), 9.27(1H, br s).

5-[4-(2-Chloro-5-methanesulfinylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-[4-[2-chloro-5-(methylthio)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(20 mg, 0.04 mmol) obtained in Example 124, the title compound (7 mg,yield 34%) was obtained in the same manner as that of Example 131.

¹H NMR (CDCl₃, 400 MHz) δ:2.75 (3H, s), 3.55 (1H, d, J=11 Hz), 3.59 (1H,d, J=11 Hz), 7.04 (1H, d, J=9 Hz), 7.23 (2H, d, J=−8 Hz), 7.5-7.8 (7H,m), 7.86 (1H, d, J=8 Hz), 7.89 (1H, d, J=2 Hz), 8.11 (1H, d, J=8 Hz),8.46 (1H, s), 8.69 (1H, s).

Example 1335-[4-(2-Methanesulfinylbenzoylamino)phenyl]1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-[4-[2-(methylthio)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(20 mg, 0.043 mmol) obtained in Example 125, the title compound (9 mg,yield 43%) was obtained in the same manner as that of Example 131.

¹H NMR (CDCl₃, 400 MHz) δ: 2.92 (3H, s), 3.59 (2H, s), 6.99 (1H, dd,J=3, 9 Hz), 7.15 (2H, t, J=8 Hz), 7.5-7.7 (5H, m), 7.71 (2H, q, J=8 Hz),7.84 (2H, dd, J=8 Hz), 8.12 (1H, dcl, J=4, 9 Hz), 8.22 (1H, dd, J=4 Hz,8 Hz), 8.7-8.9 (1H, m), 9.0-9.1 (1H, m).

Example 1345-[4-[[2-(4-Morpholinyl)acetyl]amino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione hydrochloride (1)5-[4-[(2Chloroacetyl)amino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)dione

5-(4-Aminophenyl)-1,2,3,4,8,9,10,11-octahydronaphtho[1,4]diazepine-2,4(3H,5H)-dione(64 mg, 0.2 mmol) obtained in Example 55, (6), and sodiumhydrogencarbonate (50 mg, 0.6 mmol) were suspended in chloroform (6.4mL), the suspension was added with chloroacetyl chloride (38 μL, 0.48mmol), and the mixture was stirred at room temperature for 7 hours. Thisreaction mixture was added with water, the mixture was stirred for 10minutes, and then the chloroform layer was washed with saturated brine,and dried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure, and the residue was washed with ethyl acetateand then with hexane to give the title compound (74 mg, yield 41%) asoff-white crystals.

¹H NMR (DMSO-d₆, 400 MHz) δ: 1.6-1.9 (4H, m), 2.5-2.8 (3H, m), 2.8-3.0(1H, m), 3.03 d, J=12 Hz), 3.55 (1H, d, J=12 Hz), 4.25 (2H, s), 6.62(1H, d, J=8 Hz), 6.87 (1H, d, J=8 Hz), 7.12 (2H, d, J=8 Hz), 7.62 (2H,d, J=9 Hz), 9.86 (1H, s), 10.39 (1H, s).

(2)5-[4-[[2-(4-Morpholinyl)acetyl]amino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dionehydrochloride

5-[4-[(2-Chloroacetyl)amino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(27 mg, 0.068 mmol), morpholine (30 mg, 0.34 mmol), and ethanol (6.8 mL)were mixed, and the mixture was refluxed by heating for 8 hours. Thesolvent was evaporated under reduced pressure, and the residue waswashed several times with water to give5-[4-[[2-(4-morpholinyl)acetyl]amino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(28 mg, 0.062 mmol).

This compound was dissolved in chloroform (3 mL) and methanol (1 mL),and the solution was added with a 4 M solution of hydrogen chloride inethyl acetate (0.03 mL). The solvent was evaporated under reducedpressure, and the residue was concentrated twice from ethyl acetateunder reduced pressure, and then washed with ethyl acetate to obtain thetitle compound (30 mg, yield 91%) as gray amorphous.

¹H NMR (DMSO-d₆, 400 MHz) δ: 1.6-1.9 (4H, m), 2.5-2.8 (3H, m), 2.8-3.0(1H, m), 3.03 (1H, d, J=12 Hz), 3.2-3.6 (4H, m), 3.55 (1H, d, J=12 Hz),3.7-4.1 (4H, m), 4.21 (2H, s), 6.61 (1H, d, J=8 Hz), 6.87 (1H, d, J=8Hz), 7.15 (2H, d, J=9 Hz), 7.65 (2H, d, J=9 Hz), 9.88 (1H, s), 10.67(1H, br s), 11.01 (1H, s).

Example 1355-[4-(2-Chloro-6-methoxybenzoylamino)phenyl]-1,3-dihydronaphtho[1,2-e]-1,4-diazepin-2-one

By using 5-(4-aminophenyl)-1,3-dihydronaphtho[1,2-e]-1,4-diazepin-2-one(40 mg, 0.13 mmol) obtained in Example 64, and 2-chloro-6-methoxybenzoylchloride (0.2 mmol), the title compound (51 mg, yield 54%) was obtainedin the same manner as that of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.78 (1H, d, J=10 Hz), 3.81 (3H, s), 4.55(1H, d, J=10 Hz), 7.1-7.2 (2H, m), 7.31 (1H, d, J=9 Hz), 7.43 (1H, t,J=8 Hz), 7.53 (2H, d, J=8 Hz), 7.6-7.8 (5H, m), 8.0-8.1 (1H, m), 8.36(1H, d, J=9 Hz), 10.69 (1H, s), 10.80 (1H, s).

Example 1365-[4-[[(3-Chloropyridin-2-yl)carbonyl]amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

3-Chloropyridine-2-carboxylic acid (47 mg, 0.3 mmol) was treated withthionyl chloride in dichloroethane, and then by using the resultanttogether with5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (63mg, 0.2 mmol) obtained in Example 1, (3), the title compound (41 mg,yield 45%) was obtained as pale brown crystals in the same manner asthat of Example 1, (4).

¹H NMR (CDCl₃, 400 MHz) δ: 3.61 (2H, s), 7.03 (1H, d, J=9 Hz), 7.25 (2H,d, J=9 Hz), 7.41 (1H, dd, J=4 Hz, 8 Hz), 7.5-7.6 (2H, m), 7.68 (1H, t,J=8 Hz), 7.77 (2H, d, J=9 Hz), 7.8-7.9 (2H, m), 8.24 (1H, d, J=8 Hz),8.51 (1H, dcl, J=1 Hz, 4 Hz), 9.94 (1H, s), 9.99 (1H, s).

Example 1375-[4-(2-Chloro-6-hydroxybenzoylamino)phenyl]-1,3-dihydronaphtho[1,2-e]-1,4-diazepin-2-one

By using5-[4-(2-chloro-6-methoxybenzoylamino)phenyl]-1,3-dihydronaphtho[1,2-e]-1,4-diazepin-2-one(46 mg, 0.098 mmol) obtained in Example 135, the title compound (36 mg,yield 81%) was obtained in the same manner as that of Example 18.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.78 (1H, d, J=10 Hz), 4.55 (1H, d, J=10Hz), 6.89 (1H, d, J=8 Hz), 6.94 (1H, d, J=8 Hz), 7.24 (1H, t, J=8 Hz),7.31 (1H, d, J=9 Hz), 7.52 (2H, d, J=9 Hz), 7.6-7.8 (5H, m), 8.0-8.1(1H, m), 8.36 (1H, d, J==−10 Hz), 10.27 (1H, s), 10.60 (1H, s), 10.80(1H, s).

Example 1385-[4-(3-Chloro-2-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 1, (3), and 3-chloro-2-methoxybenzoyl chloride, thetitle compound (yield 9%) was obtained in the same manner as that ofExample 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.70 (1H, d, J=12Hz), 3.84 (3H, s), 7.02 (1H, d, J=9 Hz), 7.21 (2H, d, J=8 Hz), 7.26 (1H,t, J=8 Hz), 7.4-7.7 (5H, m), 7.78 (2H, d, J=9 Hz), 7.92 (1H, d, J=8 Hz),8.25 (1H, d, J=8 Hz), 10.54 (1H, s), 10.88 (1H, br s).

Example 1395-[4-[(3-Methylpyridin-2-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 1, (3), and 3-methylpicolinic acid chloride, thetitle compound (yield 87%) was obtained in the same manner as that ofExample 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 2.57 (3H, s), 3.15 (1H, d, J=12 Hz), 3.70(1H, d, J=12 Hz), 7.02 (1H, d, J=9 Hz), 7.21 (2H, d, J=9 Hz), 7.51 (1H,dd, J=4 Hz, 7 Hz), 7.59 (1H, t, J=8 Hz), 7.6-7.7 (3H, m), 7.81 (1H, d,J=8 Hz), 7.8-8.0 (3H, m), 8.25 (1H, d, J=8 Hz), 8.54 (1H, d, J=4 Hz),10.68 (1H, s), 10.89 (1H, s).

Example 1405-[4-[[(3-Chloropyridin-2-yl)carbonyl]amino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

3-Chloropyridine-2-carboxylic acid (47 mg, 0.3 mmol) was treated withthionyl chloride in dichloroethane, and then by using the resultanttogether with5-(4-aminophenyl)-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(64 mg, 0.2 mmol) obtained in Example 55, (6), the title compound (72mg, yield 53%) was obtained as pale brown powder in the same manner asthat of Example 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 1.6-1.9 (4H, m), 2.5-2.8 (3H, m), 2.8-3.0(1H, m), 3.04 (1H, d, J=12 Hz), 3.57 (1H, d, J=12 Hz), 6.66 (1H, d, J=8Hz), 6.89 (1H, d, J=9 Hz), 7.16 (2H, d, J=9 Hz), 7.61 (1H, dd, J=4 Hz, 8Hz), 7.78 (2H, d, J=9 Hz), 8.11 (1H, dd, J=1 Hz, 8 Hz), 8.63 (1H, dd,J=1 Hz, 4 Hz), 9.89 (1H, s), 10.78 (1H, s).

Example 1415-[4-(3-Chloro-2-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-[4-(3-chloro-2-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 138, the title compound (yield 77%) was obtained inthe same manner as that of Example 18.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.16 (1H, d, J=12 Hz), 3.72 (1H, d, J=12Hz), 7.01 (2H, d, 4=9 Hz), 7.26 (2H, d, 4=9 Hz), 7.59 (1H, t, 4=7 Hz),7.6-7.7 (3H, m), 7.77 (2H, d, J=9 Hz), 7.92 (1H, d, 4=7 Hz), 8.00 (1H,dd, 4=1 Hz, 8 Hz), 8.26 (1H, d, J=8 Hz), 10.68 (1H, Jar s), 10.90 (1H,s).

Example 1425-[4-([(3-Hydroxy-pyridin-2-yl)carbonyl]amino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (63mg, 0.2 mmol), 3-hydroxypyridine-2-carboxylic acid (33 mg, 0.24 mmol),dry dimethylacetamide (6 mL), triethylamine (0.07 mL, 0.5 mmol), andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (95 mg, 0.25 mmol) were mixed, and the mixture wasstirred at room temperature for 24 hours. This reaction mixture wasadded with water, the mixture was extracted with ethyl acetate, and theorganic layer was washed with saturated brine, and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure, andthe residue was purified by silica gel column chromatography(methanol/chloroform=1/100), and then washed several times with ethylacetate to give the title compound (37 mg, yield 42%) as white crystals.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.18 (1H, d, 4=12 Hz), 3.72 (1H, d, 4=12Hz), 7.03 (1H, d, J=9 Hz), 7.26 (2H, d, J=8 Hz), 7.50 (1H, d, J=8 Hz),7.5-7.7 (2H, m), 7.67 (1H, J=8 Hz), 7.72 (1H, d, 4=9 Hz), 7.9-8.0 (3H,m), 8.2-8.3 (2H, m), 10.91 (1H, s), 11.03 (1H, s), 12.03 (1H, s).

Example 1435-[4-[(3-Vinylpyridin-2-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 1, (3), and 3-vinylpicolinic acid chloride, thetitle compound (yield 35%) was obtained in the same manner as that ofExample 1, (4).

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, 4=12 Hz), 3.70 (1H, d, 4=12Hz), 5.46 (1H, d, J=11 Hz), 5.91 (1H, d, J=17 Hz), 7.01 (1H, d, J=9 Hz),7.22 (2H, d, J=9 Hz), 7.39 (1H, dd, J=11 Hz, 17 Hz), 7.5-7.8 (4H, m),7.87 (2H, d, J=9 Hz), 7.92 (1H, d, J=8 Hz), 8.20 (1H, d, J=8 Hz), 8.25(1H, d., J=8 Hz), 8.61 (1H, dd, J=1 Hz, 5 Hz), 10.74 (1H, s), 10.89 (1H,s).

Example 1445-[4-[(3-Ethylpyridin-2-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (100mg, 0.315 mmol) obtained in Example 1, (3), HATU (180 mg, 0.473 mmol),triethylamine (132 μL, 0.945 mmol), and 3-ethylpicolinic acid (71 mg,0.473 mmol) were stirred at room temperature for 2 hours in anhydrousdimethylacetamide (10 mL). The reaction mixture was post-treated in aconventional manner to give the title compound (98 mg, yield 69%).

¹H NMR (DMSO-d₆, 400 MHz) δ: 1.20 (3H, t, J=7 Hz), 2.94 (2H, q, 3.15(1H, d, J=12 Hz), 3.70 (1H, d, J=12 Hz), 7.02 (1H, d, J=9 Hz), 7.21 (2H,d, J=9 Hz), 7.53 (1H, dd, J=4 Hz, 8 Hz), 7.59 (1H, t, J=7 Hz), 7.6-7.8(2H, m), 7.8-8.0 (4H, m), 8.25 (1H, d, J=8 Hz), 8.53 (1H, dd, J=1 Hz, 4Hz), 10.67 (1H, s), 10.89 (1H, br s).

Example 145N-[4-(2,4-Dioxo-1,2,3,4-tetrahydronaphtho[2-b][1,4]diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide

5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (40mg, 0.13 mmol) obtained in Example 1, (3), and 2-nitrobenzenesulfonylchloride (42 mg, 0.19 mmol.) were stirred at 80° C. in anhydrouspyridine (1 mL). After the disappearance of the starting materials wasconfirmed, a post-treatment was performed in a conventional manner toobtain the title compound (45 mg, yield 71%).

¹H NMR (CDCl₃, 400 MHz) δ: 3.57 (2H, s), 6.93 (1H, d, J=9 Hz), 7.1-7.2(4H, m), 7.45 (1H, s), 7.5-7.8 (5H, m), 7.86 (1H, d, J=8 Hz), 7.87 (1H,dd, J=1 Hz, 8 Hz), 7.93 (1H, dd, J=1 Hz, 8 Hz), 8.65 (1H, br s).

Example 146N-[4-(2,4-Dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]benzenesulfonamide

5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (10mg, 0.0315 mmol) obtained in Example 1, (3), and benzenesulfonylchloride (8.3 mg, 0.0473 mmol) were treated by heating in pyridine (1.0mL). After the disappearance of the starting materials was confirmed,the same treatment as that of Example 145 was performed to give thetitle compound (14 mg, yield 97%) as slightly brown amorphous.

¹H NMR (CDCl₃, 400 NHz) δ: 3.57 (2H, s), 6.78 (1H, br s), 6.93 (1H, d,J=9 Hz), 7.09 (2H, d, J=9 Hz), 7.14 (2H, d, J=9 Hz), 7.47 (2H, t, J=8Hz), 7.5-7.8 (3H, m), 7.69 (1H, t, J=8 Hz), 7.81 (2H, d, J=8 Hz), 7.86(1H, d, J=8 Hz), 8.05 (1H, d, J=9 Hz), 8.34 (1H, br s).

Example 1473-Bromo-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]benzenesulfonamide

5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 1, (3) (15 mg, 0.047 mmol), and3-bromobenzenesulfonyl chloride (24 mg, 0.095 mmol) were treated byheating in pyridine (1.0 mL). After the disappearance of the startingmaterials was confirmed, the same treatment as that of Example 145 wasperformed to give the title compound (15 mg, yield 60%) as slightlybrown amorphous.

¹H NMR (CDCl₃, 400 MHz) δ: 3.58 (2H, s), 6.81 (1H, br s), 6.94 (1H, d,J=−9 Hz), 7.10 (2H, d, J=9 Hz), 7.17 (2H, d, J=9 Hz), 7.35 (1H, t, J=8Hz), 7.5-7.8 (5H, m), 7.86 (1H, d, J=8 Hz), 7.92 (1H, t, J=2 Hz), 8.05all, d, J=8 Hz), 8.32 (1H, or s).

Example 148N-[4-(2,4-Dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-3-methoxybenzenesulfonamide

5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (10mg, 0.032 mmol) obtained in Example 1, (3), and 3-methoxybenzenesulfonylchloride (13 mg, 0.063 mmol) were treated by heating in pyridine (1.0mL). After the disappearance of the starting materials was confirmed,the same treatment as that of Example 145 was performed to obtain thetitle compound (9 mg, yield 59%) as slightly brown amorphous.

¹H NMR (CDCl₃, 400 MHz) δ: 3.57 (2H, s), 3.77 (3H, s), 6.59 (1H, s),6.94 (1H, d, J=9 Hz), 7.0-7.2 (5H, m), 7.3-7.4 (2H, m), 7.5-7.7 (3H, m),7.86 (1H, d, J=8 Hz), 8.03 (1H, d, J=8 Hz), 8.14 (1H, s).

Example 149N-[3-(2-Oxo-2,3-dihydro-1H-naphtho[1,2-e][1,4]diazepin-5-yl)phenyl]benzenesulfonamide(1) 5-(3-Bromophenyl)-1,3-dihydronaphtho[1,2-e]-1,4-diazepin-2-one

By using 1-nitro-2-naphthoaldehyde and 1-bromo-3-iodobenzene, the titlecompound was obtained in the same manner as that of the method describedin WO2008/023847.

¹H NMR (CDCl₃, 400 MHz) δ: 3.2-5.6 (2H, m), 7.2-7.4 (2H, m), 7.49 (1H,d, J=8 Hz), 7.60 (1H, d, J=8 Hz), 7.6-7.8 (31.1, m), 7.78 (1H, s), 7.95(1H, m), 8.13 (1H, m), 8.44 (1H, s).

(2) 5-(3-Aminophenyl)-1,3-dihydronaphtho[1,2-e]-1,4-diazepin-2-one

5-(3-Bromophenyl)-1,3-dihydronaphtho[1,2-e]-1,4-diazepin-2-one (50 mg,0.14 mmol) was dissolved in tetrahydrofuran (5 mL), the solution wasadded with sodium tert-butoxide (26 mg, 0.27 mmol), benzophenone imine(46 μL, 0.27 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (5 mg, 8mop, and tris(dibenzylideneacetone)dipalladium (8 mg, 8 μmol), and themixture was refluxed by heating for 5 hours under a nitrogen atmosphere.The solvent was evaporated under reduced pressure, the residue was addedwith methanol (1 mi) and 2 M hydrochloric acid (3 mi), and the mixturewas stirred at room temperature for 10 minutes. The mixture was addedwith saturated aqueous sodium hydrogencarbonate, and extracted withchloroform, and the organic layer was dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography (ethyl acetate)to give the title compound (30 mg, yield 71%) as yellow amorphous.

¹H NMR (CDCl₃, 400 MHz) δ: 3.49 (2H, s), 3.72 (2H, s), 6.78 (1H, dd, J=2Hz, 8 Hz), 6.85 (1H, d, J=8 Hz), 6.99 (1H, t, J=2 Hz), 7.16 (1H, t, J=8Hz), 7.37 (1H, d, 7.62 (1H, d, J=9 Hz), 7.6-7.7 (2H, m), 7.92 (1H, m),8.15 (1H, m), 8.63 (1H, s).

(3)N-[3-(2-Oxo-2,3-dihydro-1H-naphtho[1,2-e]-1,4-diazepin-5-yl)-phenyl]benzenesulfonamide

5-(3-Aminophenyl)-1,3-dihydronaphtho[1,2-e]-1,4-diazepin-2-one (10 mg,0.033 mmol), and benzenesulfonyl chloride (13 μL, 0.1 mmol) were treatedby heating in pyridine (1.0 mL). A post-treatment was performed in aconventional manner to give the title compound (14 mg, yield 95%) aswhite amorphous.

¹H NMR (CDCl₃, 400 MHz) δ: 6.56 (1H, s), 7.1-7.2 (2H, m), 7.2-7.5 (5H,m), 7.54 (1H, t, J=7 Hz), 7.60 (1H, d, J=9 Hz), 7.6-7.8 (4H, m), 7.9-8.0(1H, m), 8.0-8.1 (1H, m), 8.18 (1H, s).

Example 150N-[3-(2,4-Dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide

By using5-(3-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 53, (1), and 2-nitrobenzenesulfonyl chloride, thetitle compound was obtained in the same manner as that of Example 145.

¹H NMR (DMSO-de, 400 MHz) δ: 3.12 (1H, d., 3.69 (1H, d, 12 Hz), 6.75(1H, d, J=9 Hz), 6.94 (1H, s), 6.98 (1H, d, J=8 Hz), 7.0-7.1 (1H, m),7.34 (1H, t, J=8 Hz), 7.6-7.7 (4H, m), 7.77 (1H, dt, J=1 Hz, 8 Hz),7.8-8.0 (3H, m), 8.24 (1H, d, J=8 Hz), 10.76 (1H, br s), 10.90 (1H, s).

Example 151N-[4-(2,4-Dioxo-1,2,3,4,8,9,10,11-octahydro-naphtho[1,4]diazepin-5-yl)phenyl]-2-nitro-benzenesulfonamide

By using5-(4-aminophenyl)-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 55, (6), the title compound was obtained in the samemanner as that of Example 145.

¹H NMR (CDCl₃, 400 MHz) δ: 1.7-2.1 (4H, m), 2.6-2.8 (4H, m), 3.44 (1H,d, J=12 Hz), 3.49 (1H, d, J=12 Hz), 6.60 (1H, d, J=8 Hz), 6.83 (1H, d,J=8 Hz), 7.12 (2H, d, J=9H), 7.22 (2H, d, J=9H, 7.47 (1H, s), 7.62 (1H,dt, J=2 Hz, 8 Hz), 7.71 (1H, dt, J=2 Hz, 8 Hz), 7.80 (1H, br s), 7.86(1H, dd, J=2 Hz, 8 Hz), 7.91 (1H, dd, J=2 Hz, 8 Hz).

Example 152N-[4-(2,4-Dioxo-1,2,3,4,8,9,10,11-octahydro-naphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-N-methyl-2-nitrobenzenesulfonamide

N-[4-(2,4-Dioxo-1,2,3,4,8,9,10,11-octahydro-naphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-nitro-benzenesulfonamide(150 mg, 0.30 mmol) obtained in Example 151, iodomethane (22 μL, 0.36mmol), and potassium carbonate (45 mg, 0.33 mmol) were stirred inanhydrous DMF (3 mi,) for 16 hours. After the disappearance of thestarting materials was confirmed, a post-treatment was performed in aconventional manner to obtain the title compound (112 mg, yield 73%).

¹H NMR (DMSO-d₆, 400 MHz) δ: 1.6-1.9 (4H, m), 2.4-3.0 (4H, m), 3.04 (1H,d, J=12 Hz), 3.2-3.4 (3H, m), 3.57 (1H, d, J=12 Hz), 6.62 (1H, d, J=8Hz), 6.90 (1H, d, J=9 Hz), 7.16 (2H, d, J=9H), 7.27 (2H, d, J=9 Hz),7.72 (m, dd, J=1 Hz, 8 Hz), 7.80 (1H, dt, J=1 Hz, 8 Hz), 7.91 (1H, dt,J=1 Hz, 8 Hz), 7.97 (1H, d, J=8 Hz), 9.90 (1H, br

Example 153N-[3-(2,4-Dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-N-methyl-2-nitrobenzenesulfonamide

By usingN-[3-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamideobtained in Example 150, the title compound was obtained in the samemanner as that of Example 152.

¹H NMR (CDCl₃, 400 MHz) δ: 3.39 (3H, s), 3.58 (2H, s), 7.00 (m, d,7.1-7.2 (1H, m), 7.19 (1H, d, J=2 Hz), 7.2-7.3 (2H, m), 7.38 (1H, t, J=8Hz), 7.4-7.7 (6H, m), 7.87 (1H, d, J=8 Hz), 8.0-8.1 (1H, m), 8.61 (1H,br s).

Example 1544-(2,4-Dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)-N-phenylbenzenesulfonamide

By using 4-amine-N-phenylbenzenesulfonamide, the title compound wasobtained with referring to Examples 42 and 55.

¹H NMR (DMSO-d₆, 400 MHz) δ: 1.6-1.9 (4H, m), 2.6-3.0 (4H, m), 3.03 (1H,d, J=12 Hz), 3.57 (1H, d, J=12 Hz.), 6.32 (1H, d, J=8 Hz), 6.83 (1H, d,6.9-7.1 (3H, m), 7.1-7.2 (2H, m), 7.41 (1H, d, J=8 Hz), 7.45 (1H, s),7.56 (1H, t, J=8 Hz), 7.64 (1H, d, J=8 Hz), 9.92 (1H, s), 10.24 (1H, brs).

Example 155N-[3-(2,4-Dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-naphthalenesulfonamide

By using5-(3-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 53, (1), and naphthalene-2-sulfonyl chloride, thetitle compound (yield 100%) was obtained in the same manner as that ofExample 150.

¹H NMR (CDCl₃, 400 MHz) δ: 3.50 (2H, s), 6.34 (1H, s), 6.63 (1H, d, J=9Hz), 7.09 (1H, d, J=8 Hz), 7.18 (2H, d, J=9 Hz), 7.30 (1H, t, J=8 Hz),7.39 (1H, br s), 7.5-7.9 (9H, m), 8.12 (1H, d, J=8 Hz), 8.26 (1H, s),9.20 (1H, br s).

Example 156N-[3-(2,4-Dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-1-naphthalenesulfonamide

By using5-(3-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 53, (1), and naphthalene-1-sulfonyl chloride, thetitle compound (yield 100%) was obtained in the same manner as that ofExample 150.

¹H NMR (CDCl₃, 400 MHz) δ: 3.48 (2H, s), 5.82 (1H, br s), 6.47 (1H, d,7.0-7.1 (3H, m), 7.17 (1H, t, J=8 Hz), 7.29 (1H, t, J=8 Hz), 7.35 (1H,d, J=9 Hz), 7.48 (2H, t, J=8 Hz), 7.6-7.8 (3H, m), 7.81 (1H, d, J=8 Hz),7.89 (1H, d, J=8 Hz), 8.01 (1H, dd, J=1 Hz, 8 Hz), 8.15 (1H, d, J=8 Hz),8.56 (1H, d, J=9 Hz), 9.45 (1H, br s).

Example 157N-[4-(2,4-Dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]cyclohexanesulfonamide

5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30mg, 0.095 mmol) obtained in Example 1, (3), and cyclohexanesulfonylchloride (69 μL, 0.47 mmol) were treated by heating in pyridine (3 mL).A post-treatment was performed in a conventional manner to give thetitle compound (15 mg, yield 34%) as brown amorphous.

¹H NMR (CDCl₃, 400 MHz) δ: 1.1-1.4 (4H, m), 1.5-1.8 (2H, m), 1.8-2.0(2H, m), 2.1-2.3 (2H, m), 3.0-3.1 (1H, m), 3.60 (2H, s), 7.01 (1H, d,J=9 Hz), 7.2-7.4 (5H, m), 7.5-7.7 (2H, m), 7.70 (1H, t, J=7 Hz), 7.85(1H, d, J=8 Hz), 8.17 (1H, d, J=9 Hz), 9.25 (1H, br s).

Example 158N-[4-(2,4-Dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-3-pyridinesulfonamidehydrochloride

5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30mg, 0.095 mmol) obtained in Example 1, (3), and 3-pyridinesulfonylchloride (20 mg, 0.11 mmol) were treated by heating in pyridine (3 mL).A post-treatment was performed in a conventional manner to giveN-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-3-pyridinesulfonamide(40 mg).

This compound was dissolved in chloroform (1 mL) and methanol (1 mL),and the solution was added with a 4 M solution of hydrogen chloride inethyl acetate (1 mL). The solvent was evaporated under reduced pressureto obtain the title compound (43 mg, yield 87%) as white amorphous.

¹H NMR (CD₃OD, 400 MHz) δ: 3.3-3.4 (1H, m), 3.68 (1H, d, J=12 Hz), 6.96(1H, d, J=9 Hz), 7.1-7.3 (4H, m), 7.5-7.7 (3H, m), 7.8-7.9 (2H, m),7.5-7.6 (4H, m), 8.20 (1H, d, J=8 Hz), 8.49 (1H, d, J=8 Hz), 8.87 (1H,dd, J=1 Hz, 5 Hz), 9.04 (1H, d, J=2 Hz).

Example 159N-[4-(2,4-Dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-4-isopropylbenzenesulfonamide

5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32mg, 0.102 mmol) obtained in Example 1, (3), and4-isopropylbenzenesulfonyl chloride (33 mg, 0.150 mmol) were treated byheating in pyridine (2.0 mL). After the disappearance of the startingmaterials was confirmed, the same treatment as that of Example 145 wasperformed to give the title compound (29 mg, yield 58%) as whitecrystals.

¹H NMR (CDCl₃, 400 MHz) δ: 1.24 (6H, d, J=7 Hz), 2.95 (1H, m), 3.57 (2H,s), 6.75 (1H, br s), 6.94 (1H, d, J=9 Hz), 7.10 (2H, d, J=9 Hz), 7.14(2H, d, J=9 Hz), 7.32 (2H, d, J=8 Hz), 7.5-7.7 (3H, m), 7.74 (2H, d, J=9Hz), 7.86 (1H, d, J=8 Hz), 8.05 (1H, d, J=8 Hz), 8.32 (1H, br s).

Example 160N-[4-(2,4-Dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenylmethanesulfonamide

5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32mg, 0.102 mmol) obtained in Example 1, (3), and phenylmethanesulfonylchloride (29 mg, 0.150 mmol) were treated by heating in pyridine (2.0mL). After the disappearance of the starting materials was confirmed,the same treatment as that of Example 145 was performed to give thetitle compound (13 mg, yield 27%) as slightly brown amorphous.

¹H NMR (CDCl₃, 400 MHz) δ: 3.60 (2H, 8), 4.29 (2H, s), 6.32 (1H, s),7.01 (1H, d, J=9 Hz), 7.14 (2H, d, J=9 Hz), 7.2-7.3 (4H, m), 7.3-7.4(3H, m), 7.6-7.8 (3H, m), 7.87 (1H, d, J=9 Hz), 8.04 (1H, d, J=9 Hz),8.11 (1H, br s).

Example 161N-[4-(2,4-Dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-3-pyridinesulfonamide

5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30mg, 0.095 mmol) obtained in Example 1, (3), and 2-thiophenesulfonylchloride (26 mg, 0.14 mmol) were treated by heating in pyridine (3 mL).A post-treatment was performed in a conventional manner to obtain thetitle compound (27 mg, yield 61%) as white amorphous.

¹H NMR (CDCl₃, 400 MHz) δ: 3.59 (2H, s), 6.95 (1H, d, J=9 Hz), 7.01 (1H,dd, 5 Hz), 7.16 (4H, s), 7.38 (1H, s), 7.5-7.6 (4H, m), 7.69 (1H, t, J=7Hz), 7.85 (1H, d, 8.14 (1H, d, J=8 Hz), 9.03 (1H,

Example 162N-[4-(2,4-Dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-naphthalenesulfonamide

5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30mg, 0.095 mmol) obtained in Example 1, (3), and 2-naphthalenesulfonylchloride (32 rag, 0.14 mmol) were treated by heating in pyridine (3 mL).A post-treatment was performed in a conventional manner to give thetitle compound (31 mg, yield 64%) as white amorphous.

¹H NMR (CDCl₃, 400 MHz) δ: 3.56 (2H, s), 6.86 (1H, d, J=9 Hz), 7.0-7.2(4H, m), 7.24 (1H, s), 7.5-7.7 (5H, m), 7.7-8.0 (5H, m), 8.08 (1H, d,J=9 Hz), 8.38 (1H, d, J=1 Hz), 8.76 (1H, s).

Example 1634-(2,4-Dioxo-1,2,3,4,8,9,10,11-octahydronaphtho-[1,2-b][1,4]diazepin-5-yl)phenyl3-bromobenzene-sulfonate (1)N²-(4-Methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-1,2-diamine

By usingN-(4-methoxyphenyl)-1-nitro-5,6,7,8-tetrahydronaphthalene-2-amine, thetitle compound was obtained in the same manner as that of Example 55,(3).

¹H NMR (CDCl₃, 400 MHz) δ: 1.7-1.8 (2H, m), 1.8-2.0 (2H, m), 2.51 (2H,t, J=6 Hz), 2.7-2.8 (2H, m), 3.75 (3H, s), 3.7-3.8 (2H, m), 4.86 (1H, brs), 6.51 (1H, d, J=8 Hz), 6.66 (2H, d, J=9 Hz), 6.7-6.8 (2H, m), 6.85(1H, d, J=8 Hz).

(2)5-(4-Methoxyphenyl)-8,9,10,11-tetrahydro-1H-naphtho[2,1-b][1,4]diazepine-2,4(3H,5H)-dione

By using N²-(4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-1,2-diamine,the title compound was obtained in the same manner as that of Example42, (1).

¹H NMR (CDCl₃, 400 MHz) δ: 1.7-2.1 (4H, m), 2.5-2.8 (4H, m), 3.49 (2H,s), 3.81 (3H, s), 6.72 (1H, d, J=8 Hz), 6.84 (1H, d, J=8 Hz), 6.90 (2H,dt, J=2 Hz, 9 Hz), 7.12 (2H, dt, J=2 Hz, 9 Hz), 7.44 (1H, br s).

(3)5-(4-Hydroxyphenyl)-8,9,10,11-tetrahydro-1H-naphtho[2,1-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-methoxyphenyl)-8,9,10,11-tetrahydro-1H-naphtho[2,1-b][1,4]diazepine-2,4(3H,5H)-dione,the title compound was obtained in the same manner as that of Example18.

¹H NMR, 400 MHz) δ: 1.6-1.9 (4H, m), 2.5-3.0 (4H, m), 3.00 (1H, d, J=12Hz), 3.50 (1H, d, J=12 Hz), 6.63 (1H, d, J=9 Hz), 6.76 (2H, d, J=8 Hz),6.85 (1H, d, J=9 Hz), 6.93 (2H, d, J=9 Hz), 9.60 (1H, br s), 9.82 (1H,br s).

(4)4-(2,4-Dioxo-1,2,3,4,8,9,10,11-octahyclronaphtho-[1,2-b][1,4]diazepin-5-yl)phenyl3-bromobenzene-sulfonate

By using5-(4-hydroxyphenyl)-8,9,10,11-tetrahydro-1H-naphtho[2,1-b][1,4]diazepine-2,4(3H,5H)-dione,the title compound was obtained in the same manner as that of Example145.

¹H NMR (CDCl₃, 400 MHz) δ: 1.7-2.1 (4H, m), 2.6-2.8 (4H, m), 3.46 (1H,d, J=12 Hz), 3.51 (1H, d, J=12 Hz), 6.63 (1H, d, J=8 Hz), 6.87 (1H, d,J=811 z), 7.02 (1H, dt, J=2 Hz, 5 Hz), 7.17 (1H, dt, J=2 Hz, 5 Hz), 7.42(1H, t, J=8 Hz), 7.62 (1H, br s), 7.7-7.9 (1H, m), 7.99 (1H, t, J=2 Hz).

Example 164N-Benzyl-N-[4-(1-benzyl-2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide

N-[4-(2,4-Dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide(110 mg, 0.22 mmol) obtained in Example 145, dimethylformamide (1 mL),potassium carbonate (91 mg, 0.66 mmol), and benzyl bromide (31 μL, 0.26mmol) were mixed, and the mixture was stirred at room temperature for 2hours and 30 minutes. This reaction mixture was added with water, andthe mixture was extracted with ethyl acetate. The ethyl acetate layerwas washed with water, and then with saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1 to 3/2) to giveN-benzyl-N-[4-(1-benzyl-2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-nitrobenzenesolfonamide(47 mg, yield 31%) as white amorphous, andN-benzyl-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide(54 mg, yield 41%) as white amorphous.

¹H NMR (CDCl₃, 400 MHz) δ: 3.50 (1H, d, J=12 Hz), 3.58 (1H, d, J=12 Hz),4.52 (1H, d, J=14 Hz), 4.82 (1H, d, J=15 Hz), 5.02 (1H, d, J=15 Hz),6.10 (1H, d, J=14 Hz), 6.20 (2H, d, J=9 Hz), 6.66 (1H, d, J=9 Hz),6.8-7.0 (7H, m), 7.2-7.4 (4H, m), 7.5-7.8 (7H, m), 7.89 (1H, d, J=8 Hz),8.05 (1H, d, J=8 Hz).

Example 165N-Benzyl-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide

¹H NMR (CDCl₃, 400 MHz) δ: 3.56 (2H, s), 4.96 (2H, s), 6.85 (1H, d, J=9Hz), 7.12 (4H, s), 7.2-7.3 (5H, m), 7.5-7.7 (7H, m), 7.86 (1H, d, J=8Hz), 8.07 (1H, d, J=8 Hz), 8.60 (1H, s).

Example 1663-Bromo-N-[4-(2,4-dioxo-1,2,3,4-tetrahhydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-N-methylbenzenesulfonamide

By using3-bromo-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]benzenesulfonamide(78 mg, 0.145 mmol) obtained in Example 147, potassium carbonate (22 mg,0.159 mmol), and methyl iodide (11 μL, 0.177 mmol), the title compound(58 mg, yield 73%) was obtained in the same manner as that of Example152.

¹H NMR (CDCl₃, 400 MHz) δ: 3.20 (3H, s), 3.61 (2H, s), 7.01 (1H, d, J=9Hz), 7.15 (2H, d, J=9 Hz), 7.24 (2H, d, J=9 Hz), 7.36 (1H, t, J=8 Hz),7.52 (1H, d, 7.6-7.8 (5H, m), 7.88 (1H, d, J=8 Hz), 8.09 (1H, d, J=8Hz), 8.58 (1H, s).

Example 167N-[4-(2,4-Dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-N-methyl-2-nitrobenzenesulfonamide

By usingN-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamideobtained in Example 145, the title compound was obtained in the samemanner as that of Example 152.

¹H NMR (CDCl₃, 400 MHz) δ: 3.40 (3H, s), 3.61 (2H, s), 7.03 (1H, d, J=9Hz), 7.2-7.3 (4H, in), 7.5-7.8 (7H, m), 7.88 (1H, d, J=8 Hz), 8.10 (1H,d, J=8 Hz), 8.65 (1H, br s).

Example 168N-[4-(2,4-Dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-N-(2-hydroxyethyl)-2-nitrobenzenesulfonamide

By usingN-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamideobtained in Example 145, and 2-iodoethanol, the title compound wasobtained in the same manner as that of Example 152.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.4-3.5 (2H, m),3.70 (1H, d, J=1211 z), 3.78 (2H, t, J=6 Hz), 4.8-4.9 (1H, m), 6.93 (1H,d, J=9 Hz), 7.22 (2H, d, J=9 Hz), 7.27 (2H, d, J=9 Hz), 7.60 (1H, t, J=7Hz), 7.66 (1H, t, J=7 Hz), 7.7-7.8 (3H, m), 7.8-8.0 (3H, m), 8.25 (1H,d, J=8 Hz), 10.90 (1H, br s).

Example 169N-[4-(7-Chloro-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)phenyl]benzenesulfonamide(1) N-[4-(2-Amino-4-chlorophenylamino)phenyl]benzenesulfonamide

By using 4-chloro-2-nitrophenol and 4-amino-N-phenylbenzenesulfonamide,the title compound was obtained in the same manner as that of Example 1.

¹H NMR (CDCl₃, 400 MHz) δ: 3.81 (2H, be s), 5.06 (1H, be s), 6.14 (1H,br s), 6.56 (2H, d, J=9 Hz), 6.69 (1H, dd, J=2 Hz, 8 Hz), 6.77 (1H, d,J=2 Hz), 6.86 (2H, d, J=9 Hz), 6.96 (1H, d, J=9 Hz), 7.44 (2H, d, J=8Hz), 7.55 (1H, d, J=8 Hz), 7.7-7.8 (2H, m).

(2)N-[4-(7-Chloro-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)phenyl]benzenesulfonamide

By using N-[4-(2-amino-4-chlorophenylamino)phenyl]benzenesulfonamideobtained above, the title compound was obtained in the same manner asthat of Example 42.

¹H NMR (CDCl₃, 400 MHz) δ: 6.73 (1H, d, J=9 Hz), 7.02 (2H, d, 7.09 (2H,d, J=9 Hz), 7.13 (1H, dd, J=2 Hz, 9 Hz), 7.23 (1H, d, J=2 Hz), 7.5-7.7(3H, m), 7.77 (2H, d, J=7 Hz), 10.47 (1H, br s), 10.60 (1H, br

Example 170N-[4-(7-Bromo-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)phenyl]benzenesulfonamide(1) N-[4-(2-Amino-4-chlorophenylamino)phenyl]benzenesulfonamide

By using 4-bromo-2-nitrophenol and 4-amino-N-phenylbenzenesulfonamide,the title compound was obtained in the same manner as that of Example 1.

¹H NMR (CDCl₃, 400 MHz) δ: 3.73 (2H, br s), 5.12 (1H, br s), 5.92 (1H,br s), 6.54 (2H, d, J=9 Hz), 6.7-7.0 (5H, m), 7.3-7.5 (2H, m), 7.5-7.6(1H, m), 7.6-7.8 (2H, m).

(2)N-[4-(7-Bromo-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)phenyl]benzenesulfonamide

By using N-[4-(2-amino-4-bromophenylamino)phenyl]benzenesulfonamideobtained above, the title compound was obtained in the same manner asthat of Example 42.

¹H NMR (CD₃OD, 400 MHz) δ: 3.2-3.7 (2H, m), 6.76 (1H, d, J=9 Hz), 7.06(2H, d, J=9 Hz), 7.17 (2H, d, J=9 Hz), 7.24 (1H, dd, J=2 Hz, 9 Hz), 7.41(1H, d, J-2 Hz), 7.4-7.6 (3H, m), 7.7-7.9 (2H, m).

Example 171N-[4-[(2,4-Dioxo-7-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)]phenyl]benzenesulfonamide(1)N-[4-[2-Amino-4-(trifluoromethyl)phenylamino]phenyl]benzenesulfonamide

By using 2-nitro-4-(trifluorophenol and4-amino-N-phenylbenzenesulfonamide, the title compound was obtained inthe same manner as that of Example 1.

¹H NMR (CDCl₃, 400 MHz) δ: 3.80 (2H, br s), 5.38 (1H, br s), 6.69 (2H,d, J=9 Hz), 6.9-7.0 (4H, m), 7.09 (1H, d, J=8 Hz), 7.42 (2H, t, J=8 Hz),7.53 (1H, t, J=8 Hz), 7.73 (2H, d, J=8 Hz).

(2)N-[4-[2,4-Dioxo-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl]phenyl]benzenesulfonamide

By usingN-[4-[2-amino-4-(trifluoromethyl)phenylamino]phenyl]benzenesulfonamideobtained above, the title compound was obtained in the same manner asthat of Example 42.

¹H NMR (DMSO-d₆, 400 MHz) δ: 6.91 (1H, d, J=8 Hz), 7.08 (2H, d, J=9 Hz),7.13 (2H, d, J=9 Hz), 7.42 (1H, dd, J=2 Hz, 9 Hz), 7.5-7.7 (4H, m),7.7-7.8 (2H, m), 10.50 (1H, br s), 10.71 (1H, s).

Example 172N-[4-(2,4-Dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)phenyl]benzenesulfonamide

N-[4-(7-Chloro-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)phenyl]benzenesulfonamide(28 mg, 0.06 mmol) obtained in Example 169 was dissolved in methanol(0.6 mL), tetrahydrofuran (0.6 mL), and water (0.6 mL), the solution wasadded with ammonium formate (38 mg, 0.6 mmol), and the mixture wasstirred at room temperature for 16 hours. After completion of thereaction, the reaction mixture was filtered through Cerite, and thesolvent was evaporated under reduced pressure. The obtained residue wasadded with water, the mixture was extracted with chloroform, and theorganic layer was dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (chloroform/methanol=100/1) to obtainthe title compound (19 mg, yield 77%).

¹H NMR (CDs OD, 400 MHz) δ: 3.2-3.7 (2H, m), 6.84 (JH, d, J=7 Hz),7.0-7.3 (7H, m), 7.4-7.6 (3H, m), 7.79 (2H, dd, J=2 Hz, 7H z), 7.8-79(1H, m).

Example 1731-(2-Chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronanhtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 1, (3), and (2-chlorophenyl)methanesulfonylchloride, the title compound (yield 72%) was obtained in the same manneras that of Example 145.

¹H NMR (CDCl₃, 400 MHz) δ: 3.56 (2H, s), 4.63 (2H, s), 6.96 (1H, d, J=9Hz), 7.1-7.3 (6H, m), 7.42 (1H, t, J=4 Hz), 7.5-7.7 (4H, m), 7.83 d, J=8Hz), 8.17 (1H, d, J=9 Hz), 9.39 br s).

Example 1741-(3-Bromophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 1, (3), and (3-bromophenyl)methanesulfonyl chloride,the title compound (yield 92%) was obtained in the same manner as thatof Example 145.

¹H NMR (CDCl₃, 400 MHz) δ: 3.57 (2H, s), 4.30 (2H, s), 6.99 (1H, d, J=9Hz), 7.1-7.2 (5H, m), 7.42 (2H, s), 7.52 (1H, s), 7.5-7.7 (2H, m), 7.70(1H, t, J=8 Hz), 7.83 (1H, d, J=8 Hz), 8.17 (1H, d, J=8 Hz), 9.33 (1H,br s).

Example 175N-[4-(2,4-Dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-trifluoromethylbenzenesulfonamide

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 1, (3), and 2-(trifluoromethyl)benzene-1-sulfonylchloride, the title compound (yield 94%) was obtained in the same manneras that of Example 145.

¹H NMR (CDCl₃, 400 MHz) δ: 3.56 (2H, s), 6.89 (1H, d, J=9 Hz), 7.1-7.2(4H, m), 7.29 (1H, br s) 7.5-7.7 (5H m), 7.84 (1H, d, J=8 Hz), 7.88 (1H,U, J=8 Hz) 8.11 (1H, d, J=8 Hz), 8.13 (1H, d, J=8 Hz), 9.15 (1H, br s).

Example 176N-[7-Bromo-6-methyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)phenyl]benzenesulfonamide

N-[4-(2-Amino-4-bromo-3-methylphenylamino)phenyl]benzenesulfonamide (100mg, 0.231 mmol) synthesized by using 4-bromo-3-methyl-2-nitrophenol wastreated with malonyl chloride (22 μL, 0.226 mmol) in THF to give thetitle compound (12 mg, yield 10%).

NMR (CDCl₃, 400 MHz) δ: 2.52 (3H, s), 3.48 (2H, s), 6.60 (1H, d, J=9Hz), 6.95 (1H, s), 7.0-7.1 (4H, m), 7.30 (1H, d, J=9 Hz), 7.46 (2H, t,J=8 Hz), 7.56 (1H, t, J=7 Hz), 7.80 (2H, d, J=8 Hz), 7.96 (1H, s).

Example 1771-(2-Chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide

5-(4-Aminophenyl)-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(64 mg, 0.2 mmol) obtained in Example 55, (6), and2-chlorophenylmethanesulfonyl chloride (50 mg, 0.22 mmol) were treatedby heating in pyridine (0.4 mL). A post-treatment was performed in aconventional manner to give the title compound (80 mg, yield 80%) aspale brown powder.

¹H NMR (DMSO-de, 400 MHz) δ: 1.6-1.9 (4H, m), 2.5-2.8 (3H, m), (1H, m),3.02 d, 3.54 (1H, d, J=12 Hz), 4.65 (2H, s), 6.59 (1H, d, J=9 Hz), 6.90(1H, d, J=8 Hz), 7.06 (2H, d, J=8 Hz), 7.19 (2H, d, J=8 Hz), 7.3-7.4(2H, m), 7.4-7.5 (2H, m), 9.99 (1H, s), 10.17 (1H, br s).

Example 1783-Bromo-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]benzenesulfonamide

5-(4-Aminophenyl)-1,5,8,9,10,11-hexahydronaphtho[1,2-b][1,4]diazepine-2,4-dione(65 mg, 202 mmol) obtained in Example 55, and 3-bromobenzenesulfonylchloride (78 mg, 0.305 mmol) were treated by beating in pyridine (2.0mL). After the disappearance of the starting materials was confirmed,the same treatment as that of Example 145 was performed to obtain thetitle compound (47 mg, yield 43%) as white crystals.

¹H NMR (CDCl₃, 400 MHz) δ: 1.6-2.1 (4H, m), 2.5-2.9 (4H, m), 3.4-3.5(2H, br), 6.61 (1H, d, J=8 Hz), 6.84 (1H, d, J=8 Hz), 7.01 (2H, d, J=9Hz), 7.09 (2H, d, J=9 Hz), 7.33 (1H, t, J=8 Hz), 7M-7.8 (2H, m), 7.89(1H, a).

Example 179N-[4-(2,4-Dioxo-1,2,3,4,8,9,10,11-octahydronaphthe[1,2-b][1,4]diazepin-5-yl)phenyl]-3-methoxybenzenesulfonamide

5-(4-Aminophenyl)-1,5,8,9,10,11-hexahydronaphtho[1,2-b][1,4]diazepine-2,4-dione(65 mg, 0.202 mmol) obtained in Example 55, and 3-methoxybenzenesulfonylchloride (63 mg, 0.305 mmol) were treated by heating in pyridine (2.0mL). After the disappearance of the starting materials was confirmed,the same treatment as that of Example 145 was performed to give thetitle compound (48 mg, yield 48%) as white crystals.

¹H NMR (CDCl₃, 400 MHz) δ: 1.8-2.1 (4H, m), 2.5-2.8 (4H, m), 3.47 (1H,d, J=11 Hz), 3.49 (1H, d, J=11 Hz), 3.76 (3H, s), 6.60 (1H, d, J=8 Hz),6.77 (1H, s), 6.83 (1H, d, J=8 Hz), 7.0-7.2 (5H, m), 7.22 (1H, t, J=1Hz), 7.3-7.4 (2H, m), 7.58 (1H, s).

Example 1801-(2-Bromophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 1, (3), and (2-bromophenyl)methanesulfonyl chloride,the title compound (yield 46%) was obtained in the same manner as thatof Example 145.

¹H NMR (CDCl₃, 400 MHz) δ: 3.59 (2H, s), 4.69 (2H, s), 6.69 (1H, s),6.97 (1H, d, J=9 Hz), 7.1-7.2 (5H, m), 7.30 (1H, t, J=8 Hz), 7.49 (1H,d, J=8 Hz), 7.53 (1H, d, J=8 Hz), 7.5-7.8 (3H, m), 7.87 (1H, d, J=8 Hz),8.07 (1H, d, J=8 Hz), 8.43 (1H, br s).

Example 181N-[4-(2,4-Dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-1-(2-methylphenyl)methanesulfonamide

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 1, (3), and o-tolyl-methanesulfonyl chloride, thetitle compound (yield 37%) was obtained in the same manner as that ofExample 145.

¹H NMR (CDCl₃, 400 MHz) δ: 2.37 (3H, s), 3.60 (2H, s), 4.47 (2H, s),6.45 (1H, br s), 7.00 (1H, d, J=9 Hz), 7.1-7.3 (8H, m), 7.5-7.7 (2H, m),7.71 (1H, t, J=8 Hz), 7.87 (1H, d, J=8 Hz), 8.05 (1H, d, J=8 Hz), 8.24(1H, br s).

Example 182N-[4-(2,4-Dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-1-(2-nitrophenyl)methanesulfonamide

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 1, (3), and (2-nitrophenyl)methanesulfonyl chloride,the title compound (yield 41%) was obtained in the same manner as thatof Example 145.

¹H NMR (CDCl₃, 400 MHz) δ: 3.59 (2H, s), 5.00 (2H, s), 6.89 (1H, s),7.00 (1H, (1, J=9 Hz), 7.13 (2H, d, J=9 Hz), 7.18 (2H, d, J=9 Hz), 7.48(1H, d, J=8 Hz), 7.55 (1H, d, J=8 Hz), 7.5-7.7 (3H, m), 7.71 (1H, t, J=8Hz), 7.86 (1H, d, J=8 Hz), 7.99 (1H, d, J=8 Hz), 8.07 (1H, d, J=8 Hz),8.44 (1H, s).

Example 183N-[4-(2,4-Dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-phenylethanesulfonamide

By using5-(4-aminophenyl)-1H-naphtha[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 1, (3), and 2-phenylethanesulfonyl chloride, thetitle compound (yield 22%) was obtained in the same manner as that ofExample 145.

¹H NMR (CDCl₃, 400 MHz) δ: 3.16 (2H, t, J=8 Hz), 3.41 (2H, t, J=8 Hz),3.60 (2H, s), 6.20 (1H, s), 6.98 (1H, d, J=9 Hz), 7.02 (2H, d, J=9 Hz),7.1-7.4 (7H, m), 7.5-7.7 (2H, m), 7.70 (1H, t, J=8 Hz), 7.86 (1H, d, J=8Hz), 8.05 (1H, d, J=8 Hz), 8.24 (1H, s).

Example 1841-(2,3-Dichlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide

By using5-(4-aminophenyl)-1,5,8,9,10,11-hexahydronaphtho[1,2-b][1,4]diazepine-2,4-dione(32 mg, 0.100 mmol) obtained in Example 55, and(2,3-dichlorophenyl)methanesulfonyl chloride (31 mg, 0.119 mmol), thetitle compound (50 mg, yield 92%) was obtained in the same manner asthat of Example 145.

¹H NMR (DMSO-d₆, 400 MHz) δ: 1.6-1.9 (4H, m), 2.4-2.8 (3H, m), 2.8-3.0(1H, m), 3.02 (1H, d, J=12 Hz), 3.54 (1H, d, J=1.2 Hz), 4.74 (2H, s),6.60 (1H, d, J=8110, 6.90 (1H, d, J=8 Hz), 7.07 (2H, d, J=9 Hz), 7.19(2H, d, J=9 Hz), 7.36 (1H, t, J=8 Hz), 7.43 (1H, dd, J=1 Hz, J=8 Hz),7.62 (1H, d, J=8 Hz), 9.87 (1H, s), 10.21 (1H, br s).

Example 1851-(2-Chlorophenyl)-N-[4-(2,4-dioxo-7-methoxy-1H-benzo[1,2-b][1,4]diazepin-1-yl)phenyl]methanesulfonamide

By using1-(4-aminophenyl)-7-methoxy-1H-1,5-benzodiazepine-2,4(3H,5H)-dione (65mg, 0.22 mmol), and 2-chlorobenzylsulfonyl chloride (74 μL, 0.33 mmol),the title compound (23 mg, yield 13%) was obtained in the same manner asthat of Example 145.

¹H NMR (CDCl₃, 400 MHz) δ: 3.51 (2H, s), 3.82 (3H, s), 4.64 (2H, s),6.62 (1H, d, J=2 Hz), 6.68 (1H, dd, J=2 Hz, 9 Hz), 6.80 (1H, d, J=9 Hz),6.94 (1H, br s), 7.09 (2H, d, J=9 Hz), 7.12 (2H, d, J=9 Hz), 7.2-7.5(4H, m), 8.37 (1H, br s).

Example 1861-(2-Chlorophenyl)-N-[4-(2,4-dioxo-7-hydroxy-1H-benzo[1,2-b][1,4]diazepin-1-yl)phenyl]methanesulfonamide

By using1-(2-chlorophenyl)-N-[4-(2,4-dioxo-7-methoxy-1H-benzo[1,2-b][1,4]diazepin-1-yl)phenyl]methanesulfonamide(83 mg, 0.17 mmol), the title compound (14 mg, yield 17%) was obtainedin the same manner as that of Example 18.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.0-3.1 (1H, m), 3.5-3.6 (1H, m), 4.64 (2H,s), 6.5-6.7 (3H, m), 7.03 (2H, d, J=9 Hz), 7.117 (2H, d, J=9 Hz),7.3-7.5 (4H, m), 9.73 (1H, s), 10.12 (1H, br s), 10.40 (1H, s).

Example 1871-(4-Chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 1, (3), and 4-chlorobenzylsulfonyl chloride, thetitle compound (yield 56%) was obtained in Ln same manlier as that ofExample 145.

¹H NMR (CDCl₃, 400 MHz) δ: 3.60 (2H, s), 4.35 (2H, s), 6.50 (1H, br s),7.00 (1H, d, J=9 Hz), 7.15 (2H, d, J=9 Hz), 7.2-7.3 (4H, m), 7.33 (2H,4, J=8 Hz), 7.6-7.7 (2H, m), 7.71 (1H, t, J=8 Hz), 7.87 (1H, d, J=8 Hz),8.07 (1H, d., J=8 Hz), 8.39 (1H, s).

Example 1881-(2-Chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)benzyl]methanesulfonamide

By using5-[4-(aminomethyl)phenyl]-1H-naphtho[2,1-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 45, (4), and 2-chlorobenzylsulfonyl chloride, thetitle compound was obtained in the same manner as that of Example 145.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.14 (1H, d, J=12 Hz), 3.70 (1H, d, J=0.12Hz), 4.18 (2H, s), 4.50 (2H, s), 6.95 (1H, d, J=9 Hz), 7.20 (2H, d., J=8Hz), 7.3-7.4 (4H, m), 7.4-7.5 (2H, m), 7.58 (1H, t, J=7 Hz), 7.6-7.7(2H, m), 7.8-8.0 (2H, m), 8.25 (1H, d, J=8 Hz), 10.85 (1H, br s).

Example 1891-(2-Chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)-2-methoxyphenyl]methanesulfonamide

By using5-(4-amino-3-methoxyphenyl)-1H-naphtho[2,1-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 63, (3), and 2-chlorobenzylsulfonyl chloride, thetitle compound was obtained in the same manner as that of Example 145.

¹H NMR (CDCl₃, 400 MHz) δ: 3.60 (2H, s), 3.77 (3H, s), 4.62 (2H, s),6.74 (1H, dd, J=2 Hz, 9 Hz), 6.83 (1H, d, J=2 Hz), 6.90 (1H, s), 7.03(1H, d, J=9 Hz), 7.2-7.4 (3H, m), 7.46 (1H, dd, J=2 Hz, 7 Hz), 7.49 (1H,d, J=9 Hz), 7.5-7.7 (2H, m), 7.6-7.8 (1H, m), 7.87 (1H, d, J=8 Hz), 8.10(1H, d, J=8 Hz), 8.60 (1H, s).

Example 1901-(2-Chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)-2-hydroxyphenyl]methanesulfonamide

By using1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)-2-methoxyphenyl]methanesulfonamideobtained in Example 189, the title compound was obtained in the samemanner as that of Example 18.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.13 (1H, d, J=12 Hz), 3.69 (1H, d, J=12Hz), 4.64 (2H, s), 6.61 (1H, d, J=8 Hz), 6.77 (1H, s), 7.02 (1H, d, J=9Hz), 7.19 (1H, d, J=9 Hz), 7.2-7.4 (2H, m), 7.4-7.8 (5H, m), 7.93 (1H,d, J=8 Hz), 8.24 (1H, d, J=8 Hz), 9.09 (1H, br s), 10.22 (1H, br s),10.90 (1H, s).

Example 1911-(2,6-Dichlorophenyl)N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide

By using5-(4-aminophenyl)-1,5,8,9,10,11-hexahydronaphtho[1,2-b][1,4]diazepine-2,4-dione(50 mg, 0.156 mmol) obtained in Example 55, and2,6-dichlorobenzylsulfonyl chloride (81 mg, 0.312 mmol), the titlecompound (25 mg, yield 29%) was obtained in the same manner as that ofExample 145.

¹H NMR (DMSO-d₆, 400 MHz) δ: 1.6-1.9 (4H, m), 2.5-2.8 (3H, m), 2.8-3.0(1H, m), 3.02 (1H, d, J=12 Hz), 3.54 (1H, d, J=12 Hz), 4.80 (2H, s),6.57 (1H, d, J=8 Hz), 6.89 (1H, d, J=8 Hz), 7.07 (2H, d, J=9 Hz), 7.22(2H, d, J=9 Hz), 7.38 (1H, dd, J=1 Hz, J=8 Hz), 7.49 (2H, d, J=8 Hz),9.87 (1H, s), 10.35 (1H, s).

Example 1921-(2-Chlorophenyl)-N-[4-(2,4-dioxo-6-methyl-1H-benzo[1,2-b][1,4]diazepin-1-vi)phenyl]methanesulfonamide

By using1-(4-aminophenyl)-6-methyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione (20mg, 0.071 mmol), and 2-chlorobenzylsulfonyl chloride (19 mg, 0.084mmol), the title compound (32 mg, yield 96%) was obtained in the samemanner as that of Example 145.

¹H NMR (DMSO-d₆, 400 MHz) δ: 2.38 (3H, s), 3.04 (1H, d, J=12 Hz), 3.55(1H, d, J=12 Hz), 4.66 (2H, s), 6.68 (1H, d, J=8 Hz), 7.0-7.1 (3H, m),7.14 (1H, d, J=7 Hz), 7.20 (2H, d, J=9 Hz), 7.3-7.4 (2H, m), 7.4-7.5(2H, m), 10.01 (1H, s), 10.18 (1H, br s).

Example 1931-(2-Chlorophenyl)-N-[4-(2,4-dioxy-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)propyl]methanesulfonamide(1) 5-(4-Aminopropyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using N-(tert-butoxycarbonyl)-1,4-diaminopropane, the title compoundwas obtained with referring to Examples 1 and 42.

¹H NMR (CDCl₃+CD₃OD, 400 MHz) δ: 1.5-1.8 (2H, m), 2.5-2.7 (2H, m), 3.38(1H, J=12 Hz), 3.45 (1H, d, 3.7-3.9 (1H, m), 4.5-4.7 (1H, m), 7.50 (1H,d, J=9 Hz), 7.60 (1H, t, J=8 Hz), 7.68 (1H, t, J=8 Hz), 7.79 (1H, d, J=9Hz), 7.90 (1H, d, J=8 Hz), 8.01 (1H, d, J=8 Hz).

(2)1-(2-Chlorophenyl)-N-[4-(2,4-dioxy-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)propyl]methanesulfonamide

By using5-(4-aminopropyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (20mg, 0.063 mmol) obtained above, and 2-chlorobenzylsulfonyl chloride (17mg, 0.076 mmol), the title compound (10 mg, yield 35%) was obtained inthe same manner as that of Example 145.

¹H NMR (CDCl₃, 400 MHz) δ: 1.5-1.6 (1H, m), 1.7-1.8 (1H, m), 2.7-3.0(2H, m), 3.37 (1H, d, J=12 Hz), 3.42 (1H, d, J=12 Hz), 3.7-3.8 (1H, m),4.43 (2H, s), 4.4-4.6 (1H, m), 4.98 (1H, t, J=7 Hz), 7.2-7.3 (2H, m),7.3-7.4 (1H, m), 7.4-7.5 (2H, m), 7.61 (1H, t, J=7 Hz), 7.69 (1H, t, J=7Hz), 7.79 (1H, d, J=9 Hz), 7.90 (1H, d., J=8 Hz), 8.06 (1H, d, J=8 Hz),8.56 (1H, br s).

Example 1941-(2-Chlorophenyl)-N-[2-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)ethyl]methanesulfonamide

5-[2-(tert-Butoxycarbonyl)aminoethyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(10 mg, 0.027 mol) obtained in Example 72, (3) was treated withtrifluoroacetic acid in the same manner as that of Example 72, (4) togive a solution of5-(2-aminoethyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione insaturated aqueous sodium hydrogencarbonate and dichloromethane. Thissolution was added with 2-chlorobenzylsulfonyl chloride (7 mg, 0.03 mol)with stirring under ice cooling, and the mixture was stirred for 1 hourunder ice cooling, and then at room temperature for 2 hours. Thisreaction mixture was added with water, and the dichloromethane layer waswashed with saturated brine, and dried over anhydrous sodium sulfate.The solvent was evaporated, and the residue was recrystallized fromethyl acetate/hexane to obtain the title compound (7 mg, yield 56%) aspale brown crystals.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.02 (1H, d, J=12 Hz), 3.0-3.2 (2H, m),3.46 (1H, d, J=12 Hz), 3.8-3.9 (1H, m), 4.1-4.2 (1H, m), 4.4-4.5 (2H,i-n), 7.3-7.4 (2H, m), 7.4-7.6 (3H, m), 7.6-7.7 (3H, m), 7.88 (1H, d,J=9 Hz), 7.99 (1H, d, J=7 Hz), 8.20 (1H, d, J=8 Hz), 10.67 (1H, Si.

Example 195N-[4-(2,4-Dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-1-(2-iodophenyl)methanesulfonamide

By using5-(4-aminophenyl)-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dioneobtained in Example 55, (6), and 2-iodobenzylsulfonyl chloride, thetitle compound was obtained in the same manner as that of Example 145.

¹H NMR (CDCl₃, 400 MHz) δ: 1.7-2.1 (4H, m), 2.5-2.8 (4H, m), 3.48 (1H,s), 3.48 (1H, s), 4.67 (2H, s), 6.6-6.7 (1H, m), 6.65 (1H, d, J=8 Hz),6.85 (1H, d, J=8 Hz), 7.02 (1H, t, J=814 z), 7.11 (4H, s), 7.33 (1H, t,J=7 Hz), 7.47 (1H, d, J=8 Hz), 7.59 (1H, br s), 7.81 (1H, d,

Example 1961-(2-Chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-N-methylmethanesulfonamide(1)5-[4-(Methylamino)phenyl]-8,9,10,11-tetrahydro-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

N-[4-(2,4-Dioxo-1,2,3,4,8,9,10,11-octahydro-naphtho[1,2-b][1,4]diazepin-5yl)phenyl]-N-methyl-2-nitrobenzenesulfonamide (99 mg, 0.190 mmol)obtained in Example 152, thiophenol (23 μL, 0.228 mmol), potassiumcarbonate (79 mg, 0.570 mmol), and anhydrous DMF were mixed, and themixture was stirred at room temperature for 16 hours. After thedisappearance of the starting materials was confirmed, a post-treatmentwas performed in a conventional manner to give the title compound (35mg, yield 55%).

¹H NMR (CDCl₃, 400 MHz) δ: 1.6-2.1 (4H, m), 2.5-2.8 (4H, In), 2.83 (3H,s), 3.47 (2H, s), 3.81 (1H, br s), 6.58 (2H, d, J=9 Hz), 6.77 (1H, d,J=9 Hz), 6.83 (1H, d, J=9 Hz), 6.99 (2H, d, J=8 Hz), 7.43 (1H, br s).

(2)1-(2-Chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-N-methylmethanesulfonamide

By using5-[4-(methylamino)phenyl]-8,9,10,11-tetrahydro-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dionementioned above, the title compound was obtained in the same manner asthat of Example 145.

¹H NMR (CDCl₃, 400 MHz) δ: 1.7-2.1 (4H, m), 2.5-2.8 (4H, m), 3.48 (1H,s), 3.48 (1H, s), 4.56 (2H, s), 6.64 (1H, d, J=8 Hz), 6.86 (1H, d, J=8Hz), 7.11 (2H, d, J=9 Hz), 7.19 (2H, d, J=9 Hz), 7.2-7.3 (2H, m), 7.41(1H, dd, J=1 Hz, 8 Hz), 7.48 (1H, s), 7.53 (1H, dd, J=2 Hz, 7 Hz).

Example 1971-(2-Chlorophenyl)-N-[4-(2-oxo-2,3-dihydro-1H-naphtho[1,2-e][1,4]diazepin-5-yl)phenyl]methanesulfonamide

By using 5-(4-aminophenyl)-1H-naphtho[1,2-e][1,4]diazepin-2(3H)-one (30mg, 0.1 mmol) obtained in Example 64, (1), and(2-chlorophenyl)methanesulfonyl chloride (34 mg, 0.15 mmol), the titlecompound (20 mg, yield 27%) was obtained in the same manner as that ofExample 145.

¹H NMR (DMSO-d₆, 500 MHz) δ: 3.84 (1H, d, J=10 Hz), 4,61(1H, d, J=10Hz), 4.74 (2H, s), 7.26 d, J=8 Hz), 7.35 (1H, d, J=9 Hz), 7.4-7.5 (2H,m), 7.5-7.6 (4H, m), 7.7-7.8 (2H, m), 7.83 (1H, d, J=9 Hz), 8.10 (1H, d,J=9 Hz), 8.43 (1H, d, J-=9 Hz), 10.48 (1H, br 10.89 (1H, s).

Example 1981-[(2-Trifluoromethyl)phenyl]-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2b][1,4]diazepin-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(1)5-[4-(Methylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By usingN-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamideobtained in Example 145, the title compound was obtained with referringto Examples 151 and 152.

¹H NMR (CDCl₃, 400 MHz) δ: 2.85 (3H, s), 3.55 d, J=12 Hz), 3.60 (1H, d,J=12 Hz), 3.87 (1H, br s), 6.61 (2H, d, J=9 Hz), 7.05 (2H, d, J=9 Hz),7.11 (1H, d, J=9 Hz), 7.5-7.7 (3H, m), 7.84 (1H, d, J=8 Hz), 8.04 (1H,d, J=8 Hz), 8.31 (1H, s).

(2)1-[(2-Trifluoromethyl)phenyl]-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylmethanesulfonamide

5-[4-(Methylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(30 mg, 0.091 mmol) mentioned above, and2-(trifluoromethyl)benzylsulfonyl chloride (35 mg, 0.137 mmol) weretreated by heating in pyridine (2.0 mL). After the disappearance of thestarting materials was confirmed, the same treatment as that of Example145 was performed to give the title compound (25 mg, yield 50%) as whitecrystals.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.17 (1H, d, J=12 Hz), 3.73 (1H, d, J=12Hz), 4.69 (2H, s), 6.96 (1H, d, J=9 Hz), 7.27 (2H, d, J=8 Hz), 7.49 (2H,d, J=8 Hz), 7.6-7.8 (6H, m), 7.79 (1H, d, J=8 Hz), 7.95 (1H, d, J=8 Hz),8.27 (1H, d, 10.95 (1H, br s).

Example 1991-(2-Ethylphenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylmethanesulfonamide

5-[4-(Methylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(40 mg, 0.121 mmol) obtained in Example 198, (1), and2-ethylbenzylsulfonyl chloride (132 mg, 0.605 mmol) were treated byheating in pyridine (1.0 mL). After the disappearance of the startingmaterials was confirmed, the same treatment as that of Example 145 wasperformed to obtain the title compound (10 mg, yield 16%) as whitecrystals.

¹H NMR (CDs OD, 400 MHz) δ: 1.16 (3H, t, J=8 Hz), 2.69 (2H, q, J=8 Hz),3.3-3.4 (4H, m), 3.72 (1H, d, J=12 Hz), 4.50 (2H, s), 7.05 (1H, d, J=9Hz), 7.1-7.2 (1H, m), 7.2-7.3 (4H, m), 7.3-7.4 (1H, m), 7.4-7.5 (2H, m),7.5-7.6 (1H, m), 7.6-7.7 (2H, m), 7.90 (1H, d, J=8 Hz), 8.22 (1H, d, J=8Hz).

Example 2001-(2,3-Dimethylphenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho(1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylmethanesulfonamide

5-[4-(Methylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(40 mg, 0.121 mmol) obtained in Example 198, (1), and2,3-dimethylbenzylsulfonyl chloride (132 mg, 0.605 mmol) were treated byheating in pyridine (1.0 mL). After the disappearance of the startingmaterials was confirmed, the same treatment as that of Example 145 wasperformed to give the title compound (20 mg, yield 32%) as pale yellowcrystals.

¹H NMR (DMSO-d₆, 400 MHz) δ: 2.17 (3H, s), 2.24 (3H, s), 3.15 (1H, d,J=12 Hz), 3.29 (311, 5), 3.71 (1H, d, J=12 Hz), 4.69 (2H, s), 6.96 (1H,d, J=9 Hz), 7.0-7.1 (1H, m), 7.1-7.2 (2H, m), 7.2-7.3 (2H, m), 7.3-7.4(2H, m), 7.60 (1H, t, J=7 Hz), 7.67 (1H, t, J=7 Hz), 7.72 (1H, d, J=9Hz), 7.92 (1H, t, J=8 Hz), 8.25 (1H, d, J=8 Hz), 10.93 (1H, br

Example 2012-(2-Chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylethanesulfonamide

5-[4-(Methylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,61-1)-dione(40 mg, 0.121 mmol) obtained in Example 198, (1), and(2-chlorophenyl)ethanesulfonyl chloride (132 mg, 0.605 mmol) weretreated by heating in pyridine (1.0 mL). After the disappearance of thestarting materials was confirmed, the same treatment as that of Example145 was performed to give the title compound (13 mg, yield 20%) as whitecrystals.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), (2H, m), 3.71 (1H,d, J=12 Hz), 6.96 (1H, d, J=9 Hz), 7.2-7.3 (4H, m), 7.4-7.5 (2H, m),7.51 (2H, d, J=9 Hz), 7.5-7.6 (1H, m), 7.6-7.7 (2H, m), 7.91 (1H, d, J=7Hz), 8.24 (1H, d, J=9 Hz), 10.92 (1H, br s).

Example 2021-(2-Nitrophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylmethanesulfonamide

5-[4-(Methylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(80 mg, 0.240 mmol) obtained in Example 198, (1), and2-nitrobenzylsulfonyl chloride (112 mg, 0.480 mmol) were treated byheating in pyridine (3.0 mL). After the disappearance of the startingmaterials was confirmed, the same treatment as that of Example 145 wasperformed to obtain the title compound (40 mg, yield 31%) as whitecrystals.

¹H NMR (CDs OD, 400 MHz) δ: 3.33 (3H, s), 3.36 (1H, d, J=12 Hz), 3.72(1H, d, J=12 Hz), 5.00 (2H, s), 7.06 (1H, d, J=8 Hz), 7.26 (2H, d, J=9Hz), 7.41 (2H, d, J=9 Hz), 7.5-7.6 (3H, m), 7.6-7.7 (3H, m), 7.90 (1H,d, J=8 Hz), 8.02 (1H, d, J=8 Hz), 8.21 (1H, d, J=8110.

Example 2031-(2-Aminophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylmethanesulfonamide

1-(2-Nitrophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylmethanesulfonamide(33 mg, 0.062 mmol) mentioned above was dissolved in a mixed solvent ofdichloromethane (0.5 mL) and ethyl acetate (1.5 mL), then the solutionwas added with tin(II) chloride dihydrate (70 mg, 0.310 mmol), and themixture was stirred at 30° C. for 16 hours. After the disappearance ofthe starting materials was confirmed, the reaction mixture was treatedin a conventional manner to give the title compound (26 mg, yield 31%)as white crystals.

¹H NMR (CDs OD, 400 MHz) δ: 3.27 (3H, s), 3.29 (1H, d, J=12 Hz), 3.65(1H, d, J=12 Hz), 4.39 (2H, s), 6.66 (1H, d, J=7 Hz), 6.73 (1H, d, J=7Hz), 6.97 (1H, d, J=9 Hz), 7.0-7.1 (2H, m), 7.17 (2H, dd, J=2 Hz, 7 Hz),7.35 (2H, dd, J=2 Hz, 7 Hz), 7.55 (1H, t, J=7 Hz), 7.5-7.7 (2H, m), 7.84(1H, d, J=8 Hz), 8.16 (1H, d, J=8 Hz).

Example 2041-(2-Dimethylaminophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylmethanesulfonamide

1-(2-Aminophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylmethanesulfonamide(18 mg, 0.036 mmol) mentioned above, zinc chloride (12 mg, 0.090 mmol),formalin (2.7 mg, 0.090 mmol), and sodium cyanoborohydride (5.7 mg,0.090 mmol) were dissolved in methanol, and the solution was refluxed byheating for 5 hours under a nitrogen atmosphere. After the disappearanceof the starting materials was confirmed, the reaction mixture wastreated in a conventional manner to give the title compound (8 mg, yield42%) as white crystals.

¹H NMR (CD₃OD, 400 MHz) δ: 2.54 (6H, s), 3.20 (3H, s), 3.28 (1H, d, J=12Hz), 3.65 (1H, d, J=12 Hz), 4.61 (2H, s), 6.9-7.0 (2H, m), 7.1-7.2 (3H,m), 7.2-7.3 (3H, m), 7.45 (1H, dd, J=1 Hz, 8 Hz), 7.5-7.6 (1H, m),7.6-7.7 (2H, m), 7.84 (1H, d, J=8 Hz), 8.15 (1H, d, J=8 Hz).

Example 2055-[4-[(Pyridin-4-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dionehydrochloride

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (63mg, 0.2 mmol) obtained in Example 1, (3), and isonicotinoyl chloridehydrochloride (71 mg, 0.4 mmol),5-[4-[(pyridin-4-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(43 mg, yield 50%) was obtained as pale green crystals in the samemanner as that of Example 1, (4).

This compound was dissolved in chloroform (3 mi,) and methanol (1 ma thesolution was added with 4 M hydrogen chloride in ethyl acetate (0.05mL), and the solvent was evaporated under reduced pressure. The residuewas washed with ethyl acetate to obtain the title compound (43 mg, yield94%) as yellow crystals.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.17 MI, d, 3.72 (1H, d, J=12 Hz), 7.02(1H, d, J=9 Hz), 7.26 (2H, d, J=9 Hz), 7.60 (1H, t, J=8 Hz), 7.68 (1H,t, J=8 Hz), 7.71 (1H, d, J=9 Hz), 7.86 (2H, d, J=9 Hz), 7.93 (1H, d, J=8Hz), 7.97 (2H, d, J=6 Hz), 8.27 (1H, d, J=8 Hz), 8.85 (2H, d, J=6 Hz),10.72 (1H, s), 10.91 (1H, s).

Example 2065-[4-[2-[(Pyridin-3-yl)oxy]acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)dionehydrochloride

5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32mg, 0.1 mmol) obtained in Example 1, (3), pyridin-3-yloxyacetic acidhydrochloride (23 mg, 0.12 mmol), WSC.HCl (23 mg, 0.12 mmol), and drypyridine (1 mL) were mixed, and the mixture was stirred at roomtemperature for 4 hours. This reaction mixture was added with water, andthe mixture was extracted with ethyl acetate. The ethyl acetate layerwas washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was washed with ethyl acetate and hexane to give5-[4-[2-[(pyridin-3-yl)oxy]acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(41 mg, yield 91%) as yellow crystals.

This compound was dissolved in chloroform (3 mL) and methanol (1 mL),and the solution was added with 4 M hydrogen chloride in ethyl acetate(0.05 mL). The solvent was evaporated under reduced pressure, and theresidue was washed with ethyl acetate to give the title compound (30 mg,yield 67%) as red crystals.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.15 (1H, d, J=12 Hz), 3.70 (1H, d, J=12Hz), 4.98 (2H, s), 6.98 (1H, d, J=9 Hz), 7.20 (2H, d, J=8 Hz), 7.6-′7.8(6H, m), 7.92 (2H, d, J=8 Hz), 7.93 (1H, d, J=8 Hz), 8.26 (1H, d, J=8Hz), 8.42 (1H, d, J=5 Hz), 8.63 (1H, s), 10.43 (1H, e), 10.89 (1H, s).

Example 2075-[4-[(Pyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2b][1,4]diazepine-2,4(3H,5H)dione hydrochloride

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (95mg, 0.3 mmol) obtained in Example 1, (3), and nicotinoyl chloridehydrochloride (64 mg, 0.36 mmol),5-[4-[(pyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(116 mg, yield 92%) was obtained as white crystals in the same manner asthat of Example 1, (4).

This compound was dissolved in chloroform (6 ml,) and methanol (6 mL),the solution was added with 4 M hydrogen chloride in ethyl acetate (0.1mL), and the solvent was evaporated under reduced pressure to obtain thetitle compound (129 mg) as pale yellow powder.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.17 (1H, d, J=12 Hz), 3.72 (1H, d, J=12Hz), 7.02 (1H, d, J=9 Hz), 7.26 (2H, d, J=9 Hz), 7.60 (1H, t, J=7 Hz),7.6-7.8 (3H, m), 7.87 (2H, d, J=9 Hz), 7.93 (1H, d, J=8 Hz), 8.27 (1H,d, J=8 Hz), 8.50 (1H, d, J=8 Hz), 8.85 (1H, d, J=4 Hz), 9.21 (1H, d, J=1Hz), 10.72 (1H, s), 10.91 (1H, s).

Example 2085-[4-[(2-Methylpyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dionehydrochloride

2-Methylnicotinic acid (55 mg, 0.4 mmol) was suspended in drydichloromethane (4 mL), the suspension was added with DMF (0.08 mL) andoxalyl dichloride (0.05 mL, 0.6 mmol), and the mixture was stirred atroom temperature for 21 hours. The solvent was evaporated under reducedpressure, and the residue was concentrated twice from drydichloromethane (1 mL) under reduced pressure. The resultant was addedwith 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(63 mg, 0.2 mmol) obtained in Example 1, (3), dry tetrahydrofuran (4mL), and triethylamine (0.11 mL), and the mixture was stirred at roomtemperature for 24 hours. This reaction mixture was added with saturatedaqueous sodium hydrogencarbonate, and the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated brine,and dried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (methanol/chloroform=1/20) to give5-[4-[(2-methylpyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(68 mg, yield 80%) as white crystals.

This compound was dissolved in chloroform (7 mL) and methanol (7 mL),the solution was added with 4 M hydrogen chloride in ethyl acetate (0.08and the solvent was evaporated under reduced pressure. The residue waswashed with ethyl acetate to give the title compound (60 mg, yield 81%)as pale brown crystals.

¹H NMR (DMSO-d₆, 400 MHz) δ: 2.60 (3H, s), 3.16 (1H, d, J=12 Hz), 3.72(1H, d, J=12 Hz), 7.02 (1H, d, J=9 Hz), 7.25 (2H, d, J=9 Hz), 7.5-7.7(3H, m), 7.71 (1H, d, 7.80 (2H, d, J-=9 Hz), 7.93 (1H, d, J=8 Hz),8.2-8.3 (2H, m), 8.71 (1H, d, J=5 Hz), 10.77 (1H, s), 10.90 (1H, s).

Example 209[4-[(2-Chloropyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

2-Chloronicotinic acid (63 mg, 0.4 mina was suspended in drydichloromethane (2 mL), the suspension was added with DMF (0.08 mL) andoxalyl dichloride (0.05 mL, 0.6 mmol), and the mixture was stirred atroom temperature for 20 hours. The solvent was evaporated under reducedpressure, and the residue was concentrated twice from drydichloromethane (1 mi) under reduced pressure. The resultant was addedwith 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(63 mg, 0.2 mmol) obtained in Example 1, (3), dry tetrahydrofuran (4 mL)and triethylamine (0.11 ml,), and the mixture was stirred at roomtemperature for 22 hours, and then refluxed by heating for 4 hours. Thisreaction mixture was added with saturated aqueous sodiumhydrogencarbonate, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and the residue was recrystallized from chloroform to obtainthe title compound (56 mg, yield 60%) as pale yellow crystals.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.16 (1H, d, J=12 Hz), 3.72 (1H, d, J=12Hz), 7.02 (1H, d, J=9 Hz), 7.24 (2H, d, J=9 Hz), 7.58 (1H, dd, J=5 Hz, 8Hz), 7.60 (1H, t, J=7 Hz), 7.67 (1H, t, J=7 Hz), 7.71 (1H, d, J=9 Hz),7.77 (2H, d, J=9 Hz), 7.93 (1H, d, J=7 Hz), 8.09 (1H, dd, J=2 Hz, 8 Hz),8.26 (1H, d, J=8 Hz), 8.54 (1H, dd, J=2 Hz, 5 Hz), 10.80 (1H, s), 10.90(1H, s).

Example 2105-[4-[2-[(Pyridin-2-yl)oxy]acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32mg, 0.1 mmol) obtained in Example 1, (3), 2-(pyridin-2-yloxy)acetic acid(23 mg, 0.15 mmol), HATU (23 mg, 0.15 mmol), triethylamine (0.04 mL),and dry dimethylformamide (1 mL) were mixed, and the mixture was stirredat room temperature for 2 hours. This reaction mixture was added withwater, and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure, andthe residue was purified by silica gel column chromatography(methanol/chloroform=1/50) to give the title compound (22 mg, yield 49%)as pale yellow crystals.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.14 (1H, d, J=12 Hz), 3.69 (1H, d, J=12Hz), 4.92 (2H, s), 6.9-7.1 (3H, m), 7.17 (2H, d, J=9 Hz), 7.59 (1H, t,J=7 Hz), 7.6-7.8 (5H, m), 7.91 (1H, d, J=8 Hz), 8.13 (1H, dd, J=2 Hz, 5Hz), 8.25 (1H, d, J=9 Hz), 10.24 (1H, s), 10.88 (1H, s).

Example 2115-[4-[[4-(Trifluoromethyl)pyridin-3-yl]carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2.4(3H,5H)-dione

By using 4-(trifluoromethyl)nicotinic acid (76 mg, 0.4 mmol) and5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (63mg, 0.2 mmol) obtained in Example 1, (3), the title compound wasobtained in the same manner as that of Example 149 (59 mg, yield 60%) aswhite crystals.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.17 (1H, d, J=12 Hz), 3.72 (1H, d, J=12Hz), 7.03 (1H, d, J=9 Hz), 7.25 (2H, d, J=9 Hz), 7.60 (1H, t, J=7 Hz),7.67 (1H, t, J=7 Hz), 7.71 (1H, d, J=9 Hz), 7.76 (2H, d, J=9 Hz), 7.91(1H, d, J=5 Hz), 7.93 (1H, d, J=8 Hz), 8.26 (1H, d, J=8 Hz), 8.99 (1H,d, J=5 Hz), 9.03 (1H, s), 10.91 (1H, s), 10.92 (1H, s).

Example 2125-[4-[(2-Chloropyridin-3-yl)carbonylamino]phenyl]-1H-[1,4]diazepino[2,3-f]isoquinoline-2,4(3H,5H)-dione(1) 5-Nitroisoquinolin-6-yl trifluoromethanesulfonate

6-Methoxy-5-nitroisoquinoline [WO2007-109182] (1.02 g, 5 mmol), and 48%hydrobromic acid (20 mL) were mixed, and the mixture was refluxed byheating for 16 hours. The reaction mixture was cooled to roomtemperature, and then the precipitated crystals were collected byfiltration, washed with water, combined with secondary crystals, anddried under reduced pressure to give yellow crystals (0.64 g).

This crude 5-nitro-6-isoquinolinol hydrobromide (0.64 g) was dissolvedin dry dichloromethane (6.4 mL) and triethylamine (1 ml,), the solutionwas added with trifluoromethanemethanesulfonic anhydride (0.58 mL, 3.54mmol), and the mixture was stirred at room temperature for 15 hours.This reaction mixture was added with water, and the dichloromethanelayer was washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated, and the residue was purified bysilica gel column chromatography (ethyl acetate/hexane=1/2) to obtainthe title compound (0.26 g, yield 14%) as pale yellow crystals.

¹H NMR (CDCl₃, 400 MHz) δ: 7.71 (1H, d, J-9 Hz), 7.80 (1H, d, J=6 Hz),8.32 (1H, d, J=9 Hz), 8.82 (1H, d, J=6 Hz), 9.44 (1H, s).

(2) tert-Butyl [4[(5-nitroisoquinolin-6-yl)amino]phenyl]carbamate

By using 5-nitroisoquinolin-6-yl trifluoromethanesulfonate (258 mg, 0.8mmol), and tert-butyl 4-aminophenylcarbamate (250 mg, 1.2 mmol), thetitle compound (80 mg, yield 26%) was obtained as red crystals in thesame manner as that of Example 1, (1).

¹H NMR (DMSO-d₆, 400 MHz) δ: 1.49 (9H, s), 7.2-7.3 (3H, m), 7.54 (2H, d,J=9 Hz), 8.07 (1H, d, J=9 Hz), 8.14 (1H, d, J=6 Hz), 8.55 (1H, d, J=6Hz), 9.08 (1H, s), 9.48 (1H, s), 9.98 s).

(3) Ethyl3-[[6-[[4-[(tert-butoxycarbonyl)amino]phenyl]amino]isoquinolin-5-yl]amino]-3oxopropionate

By using tert-butyl [4-[(5-nitroisoquinolin-6-yl)amino]phenyl]carbamate(80 mg, 0.21 mmol), a crude product of tert-butyl[4[(5-aminoisoquinolin-6-yl)amino]phenyl]carbamate was obtained as darkbrown oil in the same manner as that of Example 1, (2).

By using this crude product, the title compound (60 mg, yield 61%) wasobtained as yellow powder in the same manner as that of Example 1, (3).

¹H NMR (CDCl₃, 400 MHz) δ: 1.30 (3H, t, J=7 Hz), 1.51 (9H, s), 3.63 (2H,s), 4.26 (2H, q, J=7 Hz), 6.84 (1H, s), 6.95 (1H, s), 7.02 (2H, d, J=9Hz), 7.28 (2H, d, J=9 Hz), 7.42 (1H, d, J=9 Hz), 7.51 (1H, d, J=6 Hz),7.64 (1H, d, J=9 Hz), 8.34 (1H, 4, J=6 Hz), 8.93 (1H, s), 9.28 (1H, s).

(4) 5-(4-Aminophenyl)-1H-[1,4]diazepino[2,3-f]isoquinoline-2,4(3H,5H)-dione

By using ethyl3-[[6-[[4-[(tert-butoxycarbonyl)amino]phenyl]amino]isoquinolin-5-yl]amino]-3-oxopropionate(59 mg, 9.13 mmol), the title compound (7 mg, yield 17%) was obtained aspale brown powder in the same manner as that of Example 1, (3).

¹H NMR (CDCl₃, 400 MHz) δ: 3.53 (1H, d, J=11 Hz), 3.64 (1H, d, J=11 Hz),3.80 (2H, s), 6.71 (2H, d, J=9 Hz), 7.01 (2H, el, J=9 Hz), 7.23 (1H, d,J=9 Hz), 7.71 (1H, d, J=9 Hz), 7.82 (1H, d, J=6 Hz), 8.19 (1H, s), 8.71(1H, d, J=6 Hz), 9.22 (1H, s).

(5)5-[4-[(2-Chloropyridin-3-yl)carbonylamino]phenyl]-1H-[1,4]diazepino[2,3-f]isoquinoline-2,4(3H,5H)-dione

By using 2-chloronicotinic acid (32 mg, 0.2 mmol), and5-(4-aminophenyl)-1H-[1,4]diazepino[2,3-f]isoquinoline-2,4(3H,5H)-dione(6 mg, 0.02 mmol), the title compound (8 mg, yield 85%) was obtained aspale brown powder in the same manner as that of Example 149.

¹H NMR (DMSO-d₆, 400 MHz) δ: 3.19 (1H, d, J=12 Hz), 3.75 (1H, d, J=12Hz), 7.16 (1H, d, J=9 Hz), 7.26 (2H, d, J=8 Hz), 7.58 (1H, dd, J=5 Hz, 7Hz), 7.78 (2H, d, J=8 Hz), 7.88 (1H, d, J=9 Hz), 8.09 (1H, d, J=8 Hz),8.13 (1H, d, J=6 Hz), 8.54 (1H, d, J=5 Hz), 8.64 (1H, d, J=6 Hz), 9.27(1H, s), 10.80 (1H, s), 11.01 (1H, bs).

Example 2135-[4-[(2-Chloropyridin-3-yl)carbonylamino]phenyl]-8,9,10,11-tetrahydro-1H-[1,4]diazepino[2,3-f]isoquinoline-2,4(3H,5H)-dione

5-[4-[(2-Chloropyridin-3-yl)carbonylamino]phenyl]-1H-[1,4]diazepino[2,3-f]isoquinoline-2,4(3H,5H)-dione(10 mg, 0.022 mmol) was dissolved in acetic acid (0.4 mL), the solutionwas added with sodium borohydride (64 mg, 0.11 mmol), the mixture wasstirred at room temperature for 2 hours, and then further added withsodium borohydride (64 mg, 0.11 mmol), and the mixture was stirred atroom temperature for 2 hours. This reaction mixture was added withwater, made basic with sodium carbonate, and extracted three times withchloroform, and the organic layer was dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was washed with ethyl acetate to give the title compound (7 mg,yield 68%) as pale brown crystals.

¹H NMR (DMSO-d₆, 400 MHz) δ: 2.8-3.0 (2H, m), 3.0-3.1 (2H, m), 3.05 (1H,d, J=11 Hz), 3.56 (1H, d, J=11 Hz), 3.79 (1H, s), 6.67 (1H, d, J=8 Hz),6.84 (1H, d, J=8 Hz), 7.16 (2H, d, J=9 Hz), 7.57 (1H, J=5 Hz, 8 Hz),7.73 (2H, d, J=9 Hz), 7.78 (2H, d, J=8 Hz), 8.08 (1H, J=2 Hz, 8 Hz),8.54 (1H, dd, J=2 Hz, 5 Hz), 8.64 (1H, d, J=6 Hz), 9.93 (1H, s), 10.75(1H, s).

Example 2145-[4-[(2-Isopropylbenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione

By using5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32mg, 0.10 mmol) obtained in Example 1, (3), and 2-isopropylbenzoylchloride (0.20 mmol), the title compound (16 mg, yield 35%) was obtainedin the same manner as that of Example 1, (4).

¹H NMR (CDCl₃, 400 MHz) δ: 1.23 (6H, d, J=6 Hz), 3.16 (1H, d, J=12 Hz),3.2-3.3 (1H, m), 3.70 (1H, d, J=12 Hz), 7.03 (1H, d, 7.20 (2H, d, J=9Hz), 7.2-7.5 (4H, m, 7.5-7.8 (3H, m), 7.81 (2H, d, J=8 Hz), 7.92 (1H, d,J=8 Hz), 8.26 (1H, d, J=8 Hz), 10.51 (1H, s), 10.88 (1H, s).

Example 215 (P2X4 Receptor Antagonist Activity) (Test Method)

The P2X4 receptor antagonist activity of the compounds of the presentinvention was measured as follows. The 1321N1 cells stably expressinghuman P2X4 receptor were inoculated on a 96-well plate, cultured underthe conditions of 37° C. and 5% CO₂ for 24 hours, and then used forintracellular calcium measurement. Fura-2 AM, which is a calciumfluorescent indicator, was used for the intracellular calciummeasurement. Fura-2 AM dissolved in an assay buffer was added to thecells, the cells were left standing at room temperature for 45 minutesso that Fura-2 AM was incorporated into the cells, and then the platewas subjected to the fluorescence measurement. The treatment of thecells with each test substance was performed 15 minutes before theaddition of ATP, and inflow of calcium into the cells as a responseinduced by the addition of ATP was measured over time by using amicroplate reader. The ratio of fluorescence values obtained withexcitation lights of 340 nm and 380 nm was used as an index of thechange of intracellular calcium level, and the inhibition activity ofthe test substance was calculated on the basis of the comparison withthe value obtained in the absence of the test substance (control).

(Test Results)

TABLE 22 Test compound Inhibitory activity IC₅₀ (μM) Example 13 0.54Example 20 1.2 Example 48 0.43 Example 106 1.8 Example 173 0.064 Example196 0.97 Example 197 0.44 Paroxetine 4.0

As clearly seen from the results shown in Table 22, it was found thatthe compounds of the present invention have superior P2X4 receptorantagonist activity.

Example 216

In the same manner as that of Example 215, the compounds of Examples118, and 208 to 210 were tested for the P2X4 receptor antagonistactivity, and the results shown in Table 23 were obtained.

TABLE 23 Test compound Inhibitory activity IC₅₀ (μM) Example 118 1.1Example 208 1.3 Example 209 0.94 Example 210 1.4

As clearly seen from the results shown in Table 23, it was found thatthe compounds of the present invention described in the examples havesuperior P2X4 receptor antagonist activity.

Example 217 (Analgesic Activity)

The analgesic activity of the compounds of the present invention wasmeasured by the following method.

Preparation of Neurogenic Pain Model (Modified Chung Model)

Neurogenic pain model (modified Chung model) was prepared according tothe description of Non-patent document 9. More specifically, underisoflurane anesthesia, back hair of rats was extensively shaved, theshaved parts were wiped with rubbing alcohol, the rats were fixed on anincubator in the abdominal position, and the skins were cut and openedalong the dorsal median line on the upper and lower sides of thesacroiliac bone. The left lateral paravertebral muscle was separated inthe sacral region, and then the ligament was separated. The sacroiliaerim and the upper part thereof were cut and opened along the pyramid,the L5 nerve was ligated, and the nerve was cut on the peripheral side.The operative wound was sutured, and infection was prevented byintraperitoneal injection of Luinesin after the operation.

The pain threshold value (paw withdrawal threshold (g)) was calculatedaccording to the up down method by stimulating the sole with a von Freyfilament (Stoelting Co., TOUCH-TEST SENSORY EVALUATOR) and determiningpresence or absence of withdrawal response. The rats that showed a 50%pain threshold value of 5 g or lower in the von Frey filament test weredetermined to have allodynia.

Up Down Method and Calculation Method of 50% Threshold Value

As the von Frey filaments, seven filaments giving different stimulationstrengths were used. The 50% threshold value was calculated according tothe up down method by referring to the method of Chaplan et al. (ChaplanS R, Bach F W, Pogrel J W, Chung J M, Yaksh Quantitative assessment oftactile allodynia in the rat paw, J. Neurosci. Methods, 53:55-63 (1994).

Evaluation Method and Results

The efficacy was evaluated by orally administering the compounds ofExamples 48 and 118 using an oral feeding needle to rats on the day 9after the modified Chung operation, and observing the influence on thepain threshold value determined by the von Frey filament test. As aresult, oral administration of 50 mg/kg of the compounds of Examples 48and 118 raised the pain threshold value of the diseased limb, and it wasobserved that there was a significant difference compared with theresult for the vehicle group.

1-11. (canceled)
 12. A method of treating pain comprising administeringa therapeutically effective amount of a compound having the followingformula (II), or a pharmacologically acceptable salt thereof, to asubject in need thereof:

wherein, R¹ and R² may be the same or different, and represent ahydrogen atom, an alkyl group having 1 to 8 carbon atoms, a cycloalkylgroup having 3 to 8 carbon atoms, an alkenyl group having 2 to 8 carbonatoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having1 to 8 carbon atoms and substituted with 1 to 3 halogen atoms, an alkoxygroup having 1 to 8 carbon atoms and substituted with 1 to 3 halogenatoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group,an amino group, an alkylamino group having 1 to 8 carbon atoms, adialkylamino group having 2 to 8 carbon atoms, a carboxamido grouphaving 2 to 8 carbon atoms, a carboxyl group, an alkanoyl group having 2to 8 carbon atoms, an alkoxycarbonyl group which has 1 to 8 carbon atomsin the alkoxy moiety, a phenyl group which may be substituted, a pyridylgroup which may be substituted, or an aralkyl group which has 6 to 10carbon atoms in the aryl moiety and 1 to 8 carbon atoms in the alkylenemoiety, wherein the substituents on the phenyl group which may besubstituted and the pyridyl group which may be substituted are a halogenatom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms andsubstituted with 1 to 3 halogen atoms, or an alkoxy group having 1 to 8carbon atoms and substituted with 1 to 3 halogen atoms, or R¹ and R² maybind together to form a condensed ring selected from naphthalene ring,quinoline ring, isoquinoline ring, tetrahydronaphthalene ring, indanering, tetrahydroquinoline ring, and tetrahydroisoquinoline ring togetherwith the benzene ring to which they bind, and the ring constituted by R¹and R², bound to each other, together with the carbon atoms to which R¹and R² bind may be substituted with 1 to 4 of the same or differentsubstituents selected from an alkyl group having 1 to 8 carbon atoms, acycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkylgroup having 1 to 8 carbon atoms and substituted with 1 to 3 halogenatoms, an alkoxy group having 1 to 8 carbon atoms and substituted with 1to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, acyano group, an amino group, an alkylamino group having 1 to 8 carbonatoms, a dialkylamino group having 2 to 8 carbon atoms, a carboxamidogroup having 2 to 8 carbon atoms, a carboxyl group, an alkanoyl grouphaving 2 to 8 carbon atoms, an alkoxycarbonyl group which has 1 to 8carbon atoms in the alkoxy moiety, or an aralkyl group which has 6 to 10carbon atoms in the aryl moiety and 1 to 8 carbon atoms in the alkylenemoiety, R³ and R⁴ may be the same or different, and represent a hydrogenatom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, analkyl group having 1 to 8 carbon atoms and substituted with 1 to 3halogen atoms, an alkoxy group having 1 to 8 carbon atoms andsubstituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group,a nitro group, a cyano group, an amino group, an alkylamino group having1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, acarboxamido group having 2 to 8 carbon atoms, carboxyl group, analkanoyl group having 2 to 8 carbon atoms, an alkoxycarbonyl group whichhas 1 to 8 carbon atoms in the alkoxy moiety, or an aralkyl group whichhas 6 to 10 carbon atoms in the aryl moiety and 1 to 8 carbon atoms inthe alkylene moiety, R⁵ represents a hydrogen atom, an alkyl grouphaving 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms,an alkyl group having 1 to 8 carbon atoms and substituted with 1 to 3halogen atoms, an alkyl group having 1 to 8 carbon atoms and substitutedwith hydroxyl group, or an aralkyl group which has 6 to 10 carbon atomsin the aryl moiety and 1 to 8 carbon atoms in the alkylene moiety, R⁶and R⁷ may be the same or different, and represent a hydrogen atom, analkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl grouphaving 1 to 8 carbon atoms and substituted with 1 to 3 halogen atoms, analkoxy group having 1 to 8 carbon atoms and substituted with 1 to 3halogen atoms, a halogen atom, a hydroxyl group, or an amino group, Arepresents a phenylene group, which may have 1 to 4 of the same ordifferent substituents selected from an alkyl group having 1 to 8 carbonatoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy grouphaving 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atomsand substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8carbon atoms and substituted with 1 to 3 halogen atoms, a halogen atom,a hydroxyl group, a nitro group, a cyano group, an amino group, analkylamino group having 1 to 8 carbon atoms, a dialkylamino group having2 to 8 carbon atoms, an aralkyl group which has 6 to 10 carbon atoms inthe aryl moiety and 1 to 8 carbon atoms in the alkylene moiety, a phenylgroup, and a pyridyl group, as a substituent, B represents NHCONH,CON(R⁸), NHC(═S)NH, N(R⁹)SO₂, SO₂N(R¹⁰), or OSO₂, wherein R⁸, R⁹, andR¹⁰ independently represent a hydrogen atom, an alkyl group having 1 to8 carbon atoms, an alkyl group having 1 to 8 carbon atoms andsubstituted with 1 to 3 halogen atoms, an alkyl group having 1 to 8carbon atoms and substituted with hydroxyl group, or an aralkyl groupwhich has 6 to 10 carbon atoms in the aryl moiety and 1 to 8 carbonatoms in the alkylene moiety, D represents an alkylene chain having 1 to6 carbon atoms, which may have 1 to 4 of the same or differentsubstituents selected from an alkyl group having 1 to 8 carbon atoms, analkenyl group having 2 to 8 carbon atoms, an alkyl group having 1 to 8carbon atoms and substituted with 1 to 3 halogen atoms, an alkyl grouphaving 1 to 8 carbon atoms and substituted with hydroxyl group, and anaralkyl group in which the aryl moiety has 6 to 10 carbon atoms and thealkylene moiety has 1 to 8 carbon atoms, as a substituent, and mayfurther have a double bond, or represents an atomic bond, E representsO, or an atomic bond, G represents a piperazine, a piperidine, amorpholine, a cyclohexane, a benzene, a naphthalene, a quinoline, aquinoxaline, a benzimidazole, a thiophene, an imidazole, a thiazole, anoxazole, an indole, a benzofuran, a pyrrole, a pyridine, or apyrimidine, any of which may have 1 to 4 of the same or differentsubstituents selected from an alkyl group having 1 to 8 carbon atoms, analkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8carbon atoms, an alkyl group having 1 to 8 carbon atoms and substitutedwith 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atomsand substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxylgroup, a nitro group, a cyano group, an amino group, an alkylamino grouphaving 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbonatoms, an alkanoyl group having 2 to 8 carbon atoms, a methylenedioxygroup, a carboxyl group, an alkylsulfinyl group having 1 to 6 carbonatoms, an alkylthio group having 1 to 6 carbon atoms, an alkylsulfonylgroup having 1 to 6 carbon atoms, an aralkyl group which has 6 to 10carbon atoms in the aryl moiety and 1 to 8 carbon atoms in the alkylenemoiety, a phenyl group which may be substituted, a pyridyl group whichmay be substituted, an imidazolyl group which may be substituted, anoxazolyl group which may be substituted, and a thiazolyl group which maybe substituted, wherein the substituents on the phenyl group which maybe substituted, the pyridyl group which may be substituted, theimidazolyl group which may be substituted, the oxazolyl group which maybe substituted, and the thiazolyl group which may be substituted are ahalogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy grouphaving 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atomsand substituted with 1 to 3 halogen atoms, or an alkoxy group having 1to 8 carbon atoms and substituted with 1 to 3 halogen atoms, and mrepresents an integer of 0 to
 5. 13. The method according to claim 12,wherein A is a benzene ring, B is CONH, E is an atomic bond, and m is 0.14. The method according to claim 12, wherein A is a benzene ring, B isNHCONH, each of D and E is an atomic bond, and m is
 0. 15. The methodaccording to claim 12, wherein A is a benzene ring, B is NHC(═S)NH, eachof D and E is an atomic bond, and m is
 0. 16. The method according toclaim 12, wherein B is N(R⁹)SO₂.
 17. The method according to claim 16,wherein A is a benzene ring, E is an atomic bond, m is 0, and Drepresents an alkylene chain having 1 to 6 carbon atoms, which may have1 to 4 of the same or different substituents selected from an alkylgroup having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbonatoms, an alkyl group having 1 to 8 carbon atoms and substituted with 1to 3 halogen atoms, an alkyl group having 1 to 8 carbon atoms andsubstituted with hydroxyl group, and an aralkyl group in which the arylmoiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 8carbon atoms, as a substituent, and may further have a double bond. 18.The method according to claim 12, wherein A is a benzene ring, B isNHSO₂, and m is
 0. 19. The method according to claim 18, wherein Drepresents an alkylene chain having 1 to 6 carbon atoms, which may have1 to 4 of the same or different substituents selected from an alkylgroup having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbonatoms, an alkyl group having 1 to 8 carbon atoms and substituted with 1to 3 halogen atoms, an alkyl group having 1 to 8 carbon atoms andsubstituted with hydroxyl group, and an aralkyl group in which the arylmoiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 8carbon atoms, as a substituent, and may further have a double bond, andE is
 0. 20. The method according to claim 18, wherein D represents analkylene chain having 1 to 6 carbon atoms, which may have 1 to 4 of thesame or different substituents selected from an alkyl group having 1 to8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkylgroup having 1 to 8 carbon atoms and substituted with 1 to 3 halogenatoms, an alkyl group having 1 to 8 carbon atoms and substituted withhydroxyl group, and an aralkyl group in which the aryl moiety has 6 to10 carbon atoms and the alkylene moiety has 1 to 8 carbon atoms, as asubstituent, and may further have a double bond, and E is an atomicbond.
 21. The method according to claim 12, wherein the method oftreating pain comprises administering a therapeutically effective amountof a pharmaceutical composition comprising an effective amount of acompound of formula (II) or pharmacologically acceptable salt thereofand a pharmaceutically acceptable carrier.
 22. The method according toclaim 12, wherein the compound is selected from the group consisting ofthe following compounds: (10), (20), (24), (27), (60), (102), (103),(108), (110), (145) to (148), (150) to (192), (195), (196), and (198) to(204): (10)1-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-3-phenylthiourea;(20)1-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-3-phenylurea;(24)1-(2-chlorophenyl)-3-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]thiourea;(27)1-(2-chlorophenyl)-3-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]urea;(60)1-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-3-(2-methylphenyl)thiourea;(102)5-(4-phenylcarbamoylphenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;(103)5-(4-benzylcarbamoylphenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;(108)5-[4-(2-chlorobenzyl)carbamoylphenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;(110)5-[4-(2-chlorophenyl)carbamoylphenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;(145)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide;(146)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]benzenesulfonamide;(147)3-bromo-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]benzenesulfonamide;(148)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-3-methoxybenzenesulfonamide;(150)N-[3-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide;(151)N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydro-naphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-nitro-benzenesulfonamide;(152)N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydro-naphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-N-methyl-2-nitrobenzenesulfonamide;(153)N-[3-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-N-methyl-2-nitrobenzenesulfonamide;(154)4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)-N-phenylbenzenesulfonamide;(155)N-[3-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-naphthalenesulfonamide;(156)N-[3-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-1-naphthalenesulfonamide;(157)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]cydohexanesulfonamide;(158)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-3-pyridinesulfonamidehydrochloride; (159)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-4-isopropylbenzenesulfonamide;(160)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenylmethanesulfonamide;(161)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-3-pyridinesulfonamide;(162)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-naphthalenesulfonamide;(163)4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho-[1,2-b][1,4]diazepin-5-yl)phenyl3-bromobenzene-sulfonate; (164)N-benzyl-N-[4-(1-benzyl-2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide;(165)N-benzyl-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide;(166)3-bromo-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-N-methylbenzenesulfonamide;(167)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-N-methyl-2-nitrobenzenesulfonamide;(168)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-N-(2-hydroxyethyl)-2-nitrobenzenesulfonamide;(169)N-[4-(7-chloro-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)phenyl]benzenesulfonamide;(170)N-[4-(7-bromo-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)phenyl]benzenesulfonamide;(171)N-[4-[(2,4-dioxo-7-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)]phenyl]benzenesulfonamide;(172)N-[4-(2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)phenyl]benzenesulfonamide;(173)1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide;(174)1-(3-bromophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide;(175)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-trifluoromethylbenzenesulfonamide;(176) N-[4-(7-b romo-6-methyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)phenyl]benzenesulfonamide; (177)1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide;(178)3-bromo-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]benzenesulfonamide;(179)N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-3-methoxybenzenesulfonamide;(180)1-(2-bromophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide;(181)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-1-(2-methylphenyl)methanesulfonamide;(182)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-1-(2-nitrophenyl)methanesulfonamide; (183)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-phenylethanesulfonamide; (184)1-(2,3-dichlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide;(185)1-(2-chlorophenyl)-N-[4-(2,4-dioxo-7-methoxy-1H-benzo[1,2-b][1,4]diazepin-1-yl)phenyl]methanesulfonamide;(186) 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-7-hydroxy-1H-benzo[1,2-b][1,4]diazepin-1-yl)phenyl]methanesulfonamide; (187)1-(4-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide;(188)1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)benzyl]methanesulfonamide; (189)1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)-2-methoxyphenyl]methanesulfonamide;(190)1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)-2-hydroxyphenyl]methanesulfonamide;(191)1-(2,6-dichlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide;(192) 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-6-methyl-1H-benzo[1,2-b][1,4]diazepin-1-yl)phenyl]methanesulfonamide; (195)N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-1-(2-iodophenyl)methanesulfonamide;(196)1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-N-methylmethanesulfonamide;(198)1-[(2-trifluoromethyl)phenyl]-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylmethanesulfonamide;(199)1-(2-ethylphenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylmethanesulfonamide;(200)1-(2,3-dimethylphenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylmethanesulfonamide;(201)2-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylethanesulfonamide;(202)1-(2-nitrophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylmethanesulfonamide;(203)1-(2-aminophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylmethanesulfonamide;and (204)1-(2-dimethylaminophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylmethanesulfonamide.23. The method according to claim 12, wherein the compound isN-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]benzenesulfonamide.24. The method according to claim 12, wherein the compound is1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide.25. The method according to claim 12, wherein the compound is1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide.26. The method according to claim 12, wherein the compound is1-(2-bromophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide.27. The method according to claim 12, wherein the compound isN-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-1-(2-methylphenyl)methanesulfonamide.28. The method according to claim 12, wherein the compound isN-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-phenylethanesulfonamide.29. The method according to claim 12, wherein the compound is1-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-3-phenylurea.30. The method according to claim 12, wherein the compound is1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-N-methylmethanesulfonamide.31. The method according to claim 12, wherein the pain is nociceptivepain.
 32. The method according to claim 12, wherein the pain isinflammatory pain.
 33. The method according to claim 12, wherein thepain is neuropathic pain.
 34. The method according to claim 12, whereinthe subject is a human.